Imidazole derivatives

ABSTRACT

6-Amidinopenicillanic acid derivatives wherein one of the nitrogen atoms of the amidino group is part of a heterocyclic ring having on a side chain an unsubstituted heterocyclic ring containing 2 to 3 nitrogen atoms, and being useful as an antibiotic.

This is a divisional of application Ser. No. 568,329, filed Jan. 5,1984, now U.S. Pat. No. 4,537,969, which is a division of Ser. No.359,326, filed Mar. 18, 1982, now U.S. Pat. No. 4,431,653.

SUMMARY OF INVENTION

In accordance with this invention, it has been discovered thatpenicillanic acid derivatives of the formula: ##STR1## wherein n is aninteger from 0 to 1; ##STR2## is a saturated 5 to 7 memberedheterocyclic ring containing the one nitrogen atom as the only heteroatom in said ring, said ring being unsubstituted or substituted in oneor more positions with lower alkyl; ##STR3## is a 5 to 7 memberedheterocyclic ring which contains no additional double bond or can alsobe aromatic when it is 5-membered, said ring being either unsubstitutedor substituted in one or more positions with lower alkyl; R₁ is hydrogenor lower alkyl; ##STR4## is a 5 to 7 membered heterocyclic ring havingat most one additional nitrogen atom as the only hetero atom, from 0 totwo additional double bonds and, aside from R, either beingunsubstituted or substituted in one or more positions with a lower alkylgroup; R is selected from the group consisting of lower alkyl, nitro,hydrogen --COOH, --(CH₂)_(y) --NHR₄, --(CH₂)_(y) OR₃ and ##STR5## R₃ ishydrogen, or lower alkyl, y is an integer from 0 to 4; R₄ is hydrogen,lower alkyl, or an amino protecting group; R₅ and R₆ are hydrogen orlower alkyl, and R₇ is lower alkylene;

and/or salts of said compounds I and II; or hydrolyzable esters orhydrates thereof are useful in treating infectious diseases caused bybacterial microorganisms such as K. pneumoniae, E. coli, E. cloacae, P.aeraginosa, P. vulgaris, and S. marcescens.

DETAILED DESCRIPTION

The term "lower alkyl" designates monovalent saturated straight orbranched aliphatic hydrocarbon groups containing from 1 to 7 carbonatoms such as ethyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, with methyl and ethyl being preferred. The term "loweralkylene" designates a divalent saturated aliphatic straight or branchedchain hydrocarbon radical containing from 1 to 7 carbons such asmethylene, isopropylene, ethylene, etc. The term "halogen includes allfour halogens such as chlorine, bromine, fluorine and iodine withchlorine and bromine being preferred. The term "lower alkanoyl"designates alkanoyl groups derived from aliphatic monocarboxylic acidscontaining from 1 to 7 carbon atoms such as acetyl, propionyl, butyryl,pivaloyl, etc.

The ring ##STR6## is a saturated 5 to 7 membered heterocyclic ringcontaining the one nitrogen atom as the only hetero atom in the ring.This ring can be unsubstituted or substituted in one or more positionswith a lower alkyl group preferably methyl or ethyl. Generally, 6 to 7membered rings are preferred with a 6 membered ring being especiallypreferred. If the ring is substituted, it is generally preferred thatthe ring be substituted at one or two positions with a lower alkyl grouppreferably methyl or ethyl. The ring systems designated by ##STR7## ismost preferably piperidyl.

The ring system ##STR8## designates a 5 to 7 membered heterocyclic ring.This ring can contain additional nitrogen hetero atoms. Preferably, thisring system contains only two nitrogen atoms and from 5 to 6 members.However, ring systems containing 3 nitrogen atoms can be used in thepenicillanic acid derivative of this invention. The carbon atoms otherthan the carbon atom separating the two nitrogen atoms in the ring canbe unsubstituted or substituted with a lower alkyl group, preferablymethyl or ethyl. The carbon atom separating the two nitrogen atoms inthe ring can be substituted with any substituent designated by R. Thisring system contains a double bond between the carbon separating the twonitrogen atoms in the ring and one of these nitrogen atoms. In addition,this ring system can contain no other double bonds or can contain one ortwo additional double bonds. Among the preferred ring systems are:##STR9## where R₈ and R₈ are hydrogen or lower alkyl, preferably methylor ethyl; and R is as above.

The ring system ##STR10## is a 5 to 7 membered heterocyclic ring systemcontaining the two nitrogen atoms as the only hetero atom in the ringsystem. Generally, it is preferred that this ring system contain five orsix members. This ring system can contain only one double bond or can becompletely unsaturated, i.e. aromatic. The preferred rings designated bythe substituent are: ##STR11##

When R₄ in the compound of formula I is an amino protecting group, anyconventional amino protecting group can be utilized in the compounds ofthis invention. Any of the conventional amino protecting groups whichcan be removed by conventional acid hydrolysis or catalytichydrogenation are preferred for use in the compounds of this invention.Among the preferred amino protecting groups are included trityl,benzyloxycarbonyl, o-nitrophenylsulphenyl, t-butoxycarbonyl, benzyl,diphenylmethyl, etc.

The salts of the compounds of the invention are in addition to theirinner salts (zwitterions) mono-or dibasic salts, formed with non-toxic,pharmaceutically acceptable acids. Among these acids are includedhydrochloric acid, phosphoric acid, nitric acid, p-toluenesulphonicacid, acetic acid, propionic acid, citric acid, tartaric acid, maleicacid etc. In addition to these acids, any conventional pharmaceuticallyacceptable, non-toxic inorganic or organic acids can be used to form thesalts of the compounds of formulae I and II. These salts can be preparedby treating the compounds of formulae I and II with the aforementionedacids by conventional means well known in the art.

Also included in the invention are salts with pharmaceuticallyacceptable, non-toxic, inorganic or organic bases, e.g. alkali metalsalts and alkaline earth metal salts, for example sodium, potassium,magnesium or calcium salts, as well as salts with ammonia or suitablenon-toxic amines, such as lower alkyl amines, for example triethylamine,hydroxy-lower alkylamines, for example 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)-amine,cycloalkylamines, for example dicyclohexylamine, or benzylamines, forexample N,N'-dibenzyl-ethylenediamine, and dibenzylamine. Thus forinstance other antibiotics with acid or basic character can be used ascomponents of such salts of the compounds of formulae I and II.

The salts can also be hydrated either during manufacture or by gradualhydration of an initially anhydrous salt due to the hydroscopicproperties of the compounds of formulae I and II above.

The hydrolyzable, pharmaceutically acceptable esters of the compounds offormulae I and II are the well known types of easily hydrolyzableesters, e.g. lower alkanoyl esters, acyloxyalkyl esters, such as loweralkanoyloxyalkyl esters, e.g. acetoxymethyl and pivaloyloxymethyl estersand the corresponding 1-acetoxyethyl and 1-pivaloyloxyethyl esters,alkoxycarbonyloxyalkyl esters, e.g. methoxycarbonyloxymethyl and1-ethoxycarbonyloxyethyl esters, lactonyl esters, e.g. phthalidylesters, or lower alkoxymethyl and acylaminomethyl esters. Otheracyloxyalkyl esters are within the scope of the invention, e.g. suchesters in which the acyl group is a radical derived from a beta-lactamantibiotic, such as a penicillin, cephalosporin, an amidinopenicillanicacid or clavulanic acid, which esters when hydrolyzed in the host maygive rise to enhanced effect. Also other esters can be useful, e.g. thebenzyl ester and the cyanomethyl ester.

Appropriately the esters above can be prepared and used in the form oftheir salts with pharmaceutically acceptable, non-toxic inorganic ororganic acids or bases.

A series of substituted 6-beta-amidinopenicillanic acids, their saltsand easily hydrolyzable esters are disclosed in the British Pat. No.1,293,590 and other easily hydrolyzable esters of the compounds ofBritish Pat. No. 1,293,590 have been disclosed in the British Pat. Nos.1,335,718 and 1,405,886.

Among the pharmaceutically acceptable, non-toxic esters of theamidopenicillanic acid derivatives of formulae I and II are included thediesters of the formula: ##STR12## wherein R₁₉ is the acyl radical ofone of the compounds of formulae I and II; R₁₀ is the acyl radical ofone of the compounds of formulae I and II or an acyl radical of anotherknown beta-lactam antibiotic; and R₁₁ is hydrogen, lower alkyl, orphenyl

or salts of such esters with pharmaceutically acceptable non-toxic acidsor bases.

The compounds of formulae I and II, their salts and their hydrolyzableesters are effective in the treatment of infectious disorders caused bygram positive and gram negative bacterial microorganisms such as K.pneumoniae, E. coli, E. cloacae, P. aeruginosa, P. vulgaris and S.marcescens.

It is also an object of the present invention to provide anantibacterial pharmaceutical composition for use in the treatment ofinfectious diseases, which contains as an active ingredient a6-aminopenicillanic acid derivative of the formulae I, II, or III givenhereinbefore.

For parenteral and topical use, the compounds of formulae I, II and IIIor their salts are preferred. These can also in some cases be usedorally. However, for oral use it is in most cases advantageous to use aneasily hydrolyzable ester of the compounds, because such esters aregenerally better absorbed than the corresponding acids or salts. Theesters have no antibacterial activity per se, but they are during orafter the absorption hydrolyzed to liberate the corresponding freeacids.

The active ingredient can be used as such or can be mixed up with acarrier and/or an auxiliary agent.

In such compositions, the proportion of therapeutically active materialto carrier substance and auxiliary agent can vary between 1% and 95% byweight. The compositions can either be in any conventionalpharmaceutical form such as tablets, pills or dragees, or can be filledin medical containers such as capsules, or as far as suspensions areconcerned filled into bottles. Pharmaceutical organic or inorganic solidor liquid carriers suitable for enteral, parenteral or topicaladministration can be used to make up the composition. Gelatine,lactose, starch, magnesium stearate, talc, vegetable and animal fats andoils, gum, polyalkylene glycol, or other known carriers for medicamentsmay all be suitable as carriers.

In the pharmaceutical compositions, the compounds of the invention canbe used together with other suitable therapeutically active components,preferably with other antibacterially active compounds, such asbeta-lactam antibiotics, e.g. penicillins or other aminopenicillanicacid derivatives, and cephalosporins. Also other antibacterially activesubstances are of interest in this connection, e.g. aminoglycosides. Incombinations with beta-lactam antibiotics such as penicillins likeampicillin, amoxicillin, or carbenicillin, or cephalosporins likecephalothin, cefazolin or cephalexin, a synergistic effect is observedwhich is of importance in many clinical situations. Also a depression ofdevelopment of resistance can be obtained by a combination therapy. Insuch compositions, the weight ratio between the active componentsappropriately is between 1:20 and 20:1, preferably within the ratio 1:5and 5:1. These active components may be administered together or thecompounds of this invention may be administered before of after theadministration of another beta-lactam antibiotic.

The compounds of the invention can also be used together with abeta-lactamase inhibitor, such as clavulanic acid. Another object of theinvention resides in the selection of a dose for the compounds of theinvention which can be administered so that the desired activity isachieved without simultaneous secondary effects.

The compounds of this invention alone or in combination with otherbeta-lactam antibiotics can be conveniently administered orally indosage units amounts corresponding to from 0.025 g to 2.5 g of thesecompounds, preferably from 0.05 g to 1.5 g depending on whichmicroorganisms are involved. By the term "dosage unit" is meant aunitary, e.g. a single dose capable of being administered to a patient,and which may be readily handled and packed, remaining as a physicallystable unit dose, comprising either the active material as such or amixture of it with a pharmaceutical carrier. Generally, the oral dosageunits are administered in accordance with the patient's needs,preferably from 2 to 8 times a day and most preferably from 2 to 6 timesa day.

Similarly, for infusion, the compounds of the invention are given indoses up to 10 mg in aqueous solution.

For parenteral use, e.g. injections, the compounds of the invention orin combination with other beta-lactam antibiotics are given e.g. in anaqueous solution or suspension as a dosage unit containing from 0.1 g to2.5 g of these active compounds to be dissolved or suspended immediatelybefore use, or ready for use together with a pharmaceutically acceptablevehicle. In the form of a dosage unit these active compounds may beadministered once or more times a day at appropriate intervals, alwaysdepending, however, on the condition of the patient. As used herein theterm "patient" includes animals as well as humans. Thus, a daily dosewill preferably amount to from 0.2 g to 20 g of the compounds of theinvention alone or together with other beta-lactam antibiotics withdaily amounts of from 1 to 12 grams parenterally administered beingespecially preferred.

The compounds of the invention are appropriately administered in theform of their pharmaceutically acceptable, non-toxic, easilyhydrolyzable esters.

The compounds of formulae I and II and their salts, esters and hydrateswhen administered together or in combination with other beta-lactamantibiotics such as cephalosporins and penicillins exhibit enhancedantibacterial properties due to this combination. In general, effectsare achieved through the use of these combinations. In preparing adosage unit for oral, topical or parenteral use, the weight ratiobetween the active ingredients in a combination can vary between 1 to 20parts of an antibiotic of formulae I or II and from 20 to 1 parts ofanother beta-lactam antibiotic.

The term "non-toxic" for easily hydrolyzable esters shall mean that suchesters are therapeutically acceptable for their intended form ofadministration. In general the easily hydrolyzable esters of thecompounds of the invention are used in the oral administration, buttheir use in the parenteral administration is also within the scope ofthe invention.

The compounds of formulae I and II are prepared by reacting a compoundof the formula: ##STR13## or hydrolyzable esters or salts thereof with acompound of the formula: ##STR14## wherein R₇ and n are as above, R' isthe same as R except that the substituents designated by R containingfree amino groups are in their protected form; R¹² and R¹³ are loweralkyl or taken together form --CH₂ --(CH₂)_(x) --CH₂ -- wherein x is aninteger from 0 to 2

or a compound of the formula ##STR15## wherein n, R₇, R₁, R₁₂ and R₁₃are as above. When R₁₂ and R₁₃ are lower alkyl groups, thesesubstituents are selected from the same group.

The reaction of the compound of formula IV with either a compound offormula V or compound of formula VI can be carried out in an organicsolvent medium in the presence of a tertiary amine base. In carrying outthis reaction, any conventional inert organic solvent can be utilized.Among the preferred organic solvents are included methylene chloride,chloroform, as well as other halogenated hydrocarbons. Furthermore, incarrying out this reaction, any conventional tertiary amine base can beutilized. Among the conventional tertiary amine bases that can beutilized are included trimethylamine, triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine. In carrying out this reaction,temperature and pressure are not critical and the reaction can becarried out at room temperature and atmospheric pressure. If desired,higher or lower temperatures can be utilized.

If desired, the compounds produced by the reaction of compounds offormula IV with either the compound of formula V or VI, which contain aprotected amine substituent can be converted into the free amine by mildacid hydrolysis. Any conventional method of mild acid hydrolysis can beutilized to convert these reaction products to the compound of formula Icontaining the free amino substituent. On the other hand, the compoundof formula I where R is a nitro group can be converted to thecorresponding compound of formula I where R is NH₂ by reduction such ashydrogenation. Any conventional method of hydrogenating a nitrosubstituent to an amine can be utilized in carrying out this conversion.

On the other hand, the reaction products of either the compound offormulae V and VI with the compound of formula IV where the carboxylgroup is protected by an ester substituent can be converted to thecorresponding compounds of formulae I and II which contain free carboxylgroups by mild basic hydrolysis or hydrogenolysis. Any conventionalmethod of basic hydrolysis or hydrogenolysis can be utilized to producethe free acid of compounds of formulae I and II. If the compound offormula I and II is produced as the free acid, this compound can beesterified by any conventional means.

The compound of formula V is prepared in accordance with this inventionby first reacting a compound of the formula ##STR16## wherein X is ahalogen or a leaving group and R₇ and n are as above

with a compound of the formula ##STR17## where R' is as above to producea compound of the formula ##STR18## wherein R₇, R' and n are as above.The compound of formula IX is then converted to a compound of theformula: ##STR19## wherein R₇, R and n are as above or a salt thereofwhich is then reacted with a compound of the formula: ##STR20## whereinR¹² and R¹³ are as above to produce the compound of formula V.

The reaction of the compound of formula VII with the compound of formulaVIII to produce a compound of the formula IX is carried out in thepresence of a base and an organic solvent. Any conventional inertorganic solvent can be utilized in carrying out this reaction. Among thepreferred solvents are dimethylformamide, ethyl alcohol,dimethylsulfoxide, etc. In carrying out this reaction, any strong basecan be utilized. Among the preferred bases are included sodiumcarbonate, sodium hydride, with sodium hydride being especiallypreferred. Generally it is preferred to carry out this reaction at atemperature of from 70° C. to 150° C. In the compound of formula VII, Xcan be any conventional leaving group with mesyloxy or tosyloxy beingpreferred. On the other hand X can be a halide such as chloride orbromide.

The compound of formula IX is converted to the compound of formula X bytreating the compound of formula IX with aqueous inorganic acid such ashydrochloric acid at elevated temperatures. This reaction can be carriedout in the presence of an organic solvent. Any conventional inertorganic solvent can be utilized in carrying out this invention. Amongthe preferred inert organic solvents are included dioxane,tetrahydrofuran, etc., with dioxane being especially preferred. Incarrying out this reaction, temperatures from about 80° C. to 120° C.are generally utilized with the reflux temperature being preferred. Theuse of an acid produces the compound of formula IX in the form of itssalt which, if desired, can be neutralized with a base to form the freebase of the compound of formula IX. Either the compound of formula IX inthe form of its salt or as a free base can be utilized in the subsequentreactions to produce the compound of formula V.

Alternatively, the compound of formula IX can be converted to thecompound of formula X by treating the compound of formula IX with anorganic aqueous alkali metal hydroxide in a lower alkanol solvent. Incarrying out this reaction, temperatures of from 30° C. to 50° C. areutilized. Where R¹ in the compound of formula IX contains an amino groupprotected by means of a amino protecting group removable by acidhydrolysis such as trityl or tert-butoxy carbonyl, it is preferred toconvert the compound of formula IX to the compound of formula X bytreatment with an alkali metal hydroxide rather than an aqueousinorganic acid since treatment with an inorganic acid hydrolizes theamino protecting group.

If one treats the compound of formula IX where R' contains an aminoprotecting group with an inorganic acid to produce the compound offormula X, it is necessary to protect the free amino group again tocarry out the further reactions to produce the compound of formula V.Where R' is converted to a free amino group in the compound of formulaX, the compound of formula X contains both a primary and secondary aminegroup. Therefore, care must be taken in protecting the primary aminogroup in the compound of formula X so as not to protect the secondaryamino group. This can be done by conventional means since the primaryamino group reacts first with compounds such as trityl chloride beforethe less reactive secondary amino group. In this manner, the compound offormula X is produced having its secondary amino group free and readyfor further reaction.

Compounds of formula IX where R' is hydrogen can, if desired, beconverted to the corresponding compounds of formula IX where R' is --CH₂OH by reacting the compound of formula IX where R' is hydrogen withaqueous formaldehyde at temperatures of 120° to 200° C. in an autoclave.The compound of formulae IX and X where R' is --CH₂ OH can be converted,if desired, to the corresponding compounds of formulae IX and X where R'is --COOH by oxidation. Any conventional method of oxidizing an alkanolto an acid such as by use of oxidizing agents such as potassiumpermagnate can be used in carrying out this reaction.

If R' in the compound of formulae IX or X is nitro, this compound can beconverted to the corresponding compound of formula IX or X where R' is--NH₂ by hydrogenation such as described hereinbefore. This amino groupcan be protected in the manner described hereinbefore. On the otherhand, the amino protecting group can, if desired, be removed byconventional means from the compound of formula X.

The reaction of the compound of formula X with a compound of formula XIto produce the compound of formula V is carried out at temperatures from70° to 110° C. In carrying out this reaction, the compound of formula XImay be utilized as the reaction medium. If desired, other conventionalinert organic solvents may be present in this reaction medium. If thecompound of formula X contains a free amino group, i.e. the compound offormula X where R is --(CH₂)_(y) NH₂, this reaction produces thecompound of formula V where R' is ##STR21##

On the other hand, the compound of formula IX where R' is lower alkyl orhydrogen can be prepared by reacting a compound of the formula:##STR22## wherein R₁₄ is hydrogen or lower alkyl; and the ring ##STR23##designates a 5 to 7 membered heterocyclic ring having at most oneadditional nitrogen as the only hetero atom and from 0 to 2 additionaldouble bonds

with a compound of the formula ##STR24## wherein R₇ and n is as above ata temperature of from 120° to 150° C. This reaction is generally carriedout in the presence of catalytic amounts of a lower alkanoic acid withformic acid, acetic acid or propionic acid being preferred. In carryingout this reaction, no solvent is utilized and the reaction is carriedout by heating the compound of formula XII with the compound of formulaXIII to a temperature of from 120° C. to 150° C. in the presence ofcatalytic amounts of a lower alkanoic acid containing from 1 to 7 carbonatoms.

The compounds of formula VII are known compounds. In accordance with apreferred embodiment of this invention the compound of formula VII wheren is 1 can be prepared from compounds of the formula ##STR25## where R₇' is a lower alkylene containing from 1 to 6 carbon atoms, and n' is 0to 1

via the following intermediates ##STR26## wherein n', R₇ ' and X are asabove and the ring ##STR27## is as above.

The compound of formula XIV is converted to the compound of formula XVby reduction. Any conventional method of reducing a carboxyl group tothe corresponding hydroxy group can be utilized to carry out thisreaction. In accordance with a preferred embodiment of this invention,the compound of formula XIV is treated with diborane in an inert organicsolvent such as tetrahydrofuran. Any of the conventional conditionsutilized in reducing with diborane can be utilized to carry out thisreaction. The compound of formula XV is converted into the compound offormula XVI by treating the compound of formula XV with a halogenatingagent such as a phosphorus trihalide especially phosphorus tribromide ora compound capable of yielding a leaving group such as tosyl chloride ormesyl chloride. In carrying out this reaction any of the conditionsconventional in such reactions can be utilized in this procedure.

The compound of formula XVI is converted to the compound of formulaVII-B by treating the compound of formula XVI with acetic formicanhydride in the presence of a tertiary amine. Any of the conventionaltertiary amines such as those hereinbefore mentioned can be utilized incarrying out this invention. Generally this reaction is carried out attemperatures of from -10° to +10° C. with 0° C. being especiallypreferred.

The compound of formula VI is prepared from a compound of the formula##STR28## wherein R₇, n and X are as above and the ring ##STR29## iseither an aromatic or saturated 5 to 7 membered heterocyclic ringcontaining the nitrogen atom as the only hetero atom in the ring andbeing unsubstitued or substituted in one or more positions with loweralkyl

via the following intermediates ##STR30## wherein R₇, R₁, and n are asabove and the rings ##STR31## are as above and the ring ##STR32##designates a 5 to 7 membered heterocyclic ring which contains noadditional double bonds and unsubstituted or substituted in one or morepositions with lower alkyl; ##STR33## designates a 5 to 7 memberedaromatic heterocyclic ring containing the nitrogen atom as the onlyhetero atom in the ring and being unsubstituted or substituted in one ormore positions with lower alkyl; and R₁ is as above,

The compound of formula XVII is converted to the compound of formulaXVIII by utilizing any conventional method of converting a halide or aleaving group to a cyanide functional group. Among the preferred methodswhich can be utilized is by reacting the compound of formula XVIII withan alkali metal cyanide such as sodium cyanide. Any of the conditionsconventional in carrying out this reaction can be utilized.

In converting the compound of formula XVIII to the compound of formulaXIX, the compound of formula XVIII is reacted with a compound of theformula:

    H.sub.2 N--CHR.sub.17 --(CHR.sub.14).sub.v --(CHR.sub.15).sub.w --CHR.sub.16 --NHR.sub.1                                  XXI

wherein R₁ is as above, R₁₇, R₁₄, R₁₅ and R₁₆ are hydrogen or loweralkyl; and v and w are integers from 0 to 1.

The compound of formula XVIII is reacted with the compound of formulaXXI at temperatures of 120° C. to 250° C. in the presence of a strongacid to produce the compound of formula XIX. The preferred acid forutilization in this reaction is paratoluenesulfonic acid. However, anyconventional strong acid can be utilized. This reaction produces thecompound of formula XIX as a salt. If desired, the compound of formulaXIX can be neutralized in an inert organic solvent by the addition of abase such as sodium methoxide to produce the compound of formula XIX asa free base.

If desired, the compound of formula XIX can be converted to the compoundof formula XIX-A where both rings are aromatic by treating the compoundof formulae XIX with barium manganate or Raney Nickel. If n in thecompound of formulae XIX is 1, Raney Nickel and temperatures are fromabout 200° to about 240° C. are utilized. If n is 0, barium manganate isutilized with temperatures of from 30° C. to 100° C. with temperaturesof from about 60° C. to 80° C. being preferred. Reaction of the compoundof formula XIX with barium manganate or Raney Nickel aromatizes the ringdesignated as ##STR34## to produce ##STR35## which is the same as theformer ring except that it is aromatic.

If the ring ##STR36## in the compound of formula XIX is an aromaticring, the compound of formulae XIX and XIX-A can be converted to thecompound of formula XX by hydrogenation utilizing a conventionalhydrogenation catalyst or platinum oxide. This procedure willhydrogenate this aromatic ring without affecting the double bond betweenone of the two nitrogen atoms and the carbon which separates them in thering ##STR37## If the latter ring in the compound of formula XIX-A is afive membered ring, this hydrogenation will not affect its aromaticconfiguration. On the other hand, if this ring is a 6 or 7 memberedring, hydrogenation will affect all double bonds other than the doublebond between one of the two nitrogen atoms separated by a carbon atom.In this reduction, the hydrogenation is carried out utilizingconventional hydrogenation conditions, the preferred hydrogenationcatalyst being palladium on carbon or platinum. Any of the conventionalconditions of hydrogenation can be utilized in carrying out thisreaction.

In accordance with another embodiment of this invention, the compound offormula XX or its salt can be prepared from the known compounds of theformula: ##STR38## wherein R₇, R₁, n and the ring ##STR39## are asabove; and the ring ##STR40## is as above or its salt by hydrogenationin the same manner as disclosed hereinabove for converting a compound ofthe formula XIX-A to a compound of formula XX.

The compound of formulae XIX or XX or its salt is converted to thecompound of formula VI by reacting the compound of formulae XIX or XXwith the compound of formula XI in the same manner described inconnection with the reaction of the compound of formula X to produce thecompound of formula V.

In accordance with another embodiment of this invention, the compound offormula XIX where ##STR41## is a saturated ring can be prepared byreacting a compound of the formula: ##STR42## wherein n, and the ring##STR43## is as above with the compound of formula XXI in the presenceof a strong acid. The same conditions described hereinbefore with regardto the reaction of the compound of formula XXI with a compound offormula XVIII to produce the compound of formula XIX can be used in thisreaction.

The following Examples are illustrative but not limitative of theclaimed invention. In these Examples, the ether utilized was diethylether. The yields in these Examples are given in weight percent. In theExamples, Sephadex LH 20 designates dextran. In the Examples, alltemperatures are in degrees Centigrade.

EXAMPLE 1 4-(2-Bromoethyl)-1-piperidinecarboxaldehyde

2-(4-pyridyl)ethanol (70. g, 0.57M) and platinum oxide (2 g) in water(600 ml) and concentrated aqueous HCl (81 ml) was hydrogenated at thepressure of 1000 psig hydrogen to give 4-(2-hydroxyethyl)piperidinehydrochloride in quantitative yield. Treatment of4-(2-hydroxyethyl)piperidine hydrochloride (20 g 0.12M) with phosphorustribromide (7 ml) at 100° C. for 11/2 hr. followed by trituration withdiethyl ether (2×50 ml) and filtration gave 4(2-bromoethyl)piperidinehydrogen bromide (20.76 g, 77% yield). The solution of the4-(2-bromoethyl)piperidine hydrogen bromide (23 g.0.085M) intetrahydrofuran (170 ml) and dimethylformamide (170 ml) was prepared. Tothis solution was added formic acetic anhydride (12.7 ml) at 0° C.,followed by the addition of triethylamine (25 ml) with vigorouslystirring. The reaction mixture was stirred overnight. After thereaction, it was filtered and the filtrate was stripped in vacuo todryness and water (100 ml) was then added to the residue and the mixturewas extracted with diethyl ether (3×100 ml). Removal of the solvent andpurification on silica gel columns, eluted with ethyl acetate-hexane(9:1 parts by volume) gave 4-(2-bromoethyl)-1-piperidinecarboxaldehyde(12.06 g, 66% yield).

EXAMPLE 2 4-[2-(1H-Imidaz-1-yl)ethyl]piperidine hydrate dihydrochloride

To a mixture of imidazole (4.5 g, 65.8 mM) and sodium hydride (50% byweight in mineral oil, 3.15 g, 66 mM) at 50° C. was added4-(2-bromoethyl)-1-piperidine carboxaldehyde (12 g, 55 mM) and thereaction was heated at 50° C. for 3 hrs. The solvent was removed invacuo and water (about 100 ml) was added to the residue and then themixture was extracted with methylene chloride (3×100 ml). The combinedextracts, dried over Na₂ SO₄, were stripped to dryness and purified onsilica gel columns, eluted with methanol-methylene chloride (1:9 partsby volume) to give an oil (10.4 g) which was then refluxed with 2Nhydrochloride acid (55 ml) in dioxane (400 ml) for 5 hrs. The solventwas removed and the product was crystallized from ethanol diethyl etheryield 4-[2-(1H-imidaz-1-yl)ethyl]piperidine-hydrate-dihydrochloride inoverall yield of 55%. 8.2 g of4-[2-(1H-imidaz-1-yl)ethyl]piperidine-hydratedihydrochloride wasconverted to free base by dissolving in water (100 ml) at pH 11 andextracting with methylene chloride. Evaporation of the methylenechloride extracts in vacuo gave 5.1 g of free base.

EXAMPLE 3[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(1H-Imidazol-1-yl)ethyl]-1-piperidinyl]methylene]amino]3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate hydrochloride

The free base 4[2-(imidazol-1-yl)ethyl]piperidine (5.1 g, 28.7 mM) anddimethylformamide dimethyl acetal (23 ml) was heated at 100° C. for 6hours. Removal of the excess of dimethylformamide dimethyl acetal gave4-[2-(imidazol-1-yl)ethyl]-1-piperidine carboxaldehyde dimethylacetal(6.32 g, 87%) which was dissolved in CH₂ Cl₂ (27 ml) and added to themixture of 6-aminopenicillanic acid (5.6 g, 258 mM) anddiisopropylethylamine (3.41 ml) in CH₂ Cl₂ (100 ml) at 0° C. Thereaction was stirred at 0° C. for 1 hr. and room temperature for 3 hrs.The solvent was then removed and water (100 ml) was added. After beingwashed with ethylacetate, the aqueous solution, acidified to pH 3, waspurified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(1H-imidazol-1-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate hydrochloride (1.8 g, 16% yield).

EXAMPLE 44-[(2-Nitro-1H-Imidazol-1-yl)methyl]-1-Piperidinecarboxaldehyde

The mixture of 2-nitroimidazole (4.5 g, 40 mM) and 50% by weight NaH inmineral oil (1.92 g, 41 mM) in dimethylformamide (40 ml) was stirred atroom temperature for 1/2 hr. A solution of4-bromomethyl-1-piperidinecarboxaldehyde (8.3 g, 40 mM) indimethylformamide (10 ml) was added to the above mixture and heated at120° C. for 1/2 hr. After the reaction, solvent was removed in vacuo andwater (50 ml) was added and the mixture was extracted with ethylacetate(2×75 ml). The extracts, dried over Na₂ SO₄ was stripped to drynesswhich was then purified on silica gel column, eluted with 5% volumeMeOH-95% volume CH₂ Cl₂, to give4[(2-nitro-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde (2.4 g,10 mL) in 25% yield.

EXAMPLE 5 [2S-(2alpha,5alpha,6beta)]-3,3-Dimethyl-6-[[[4-[(2-nitro-1H-imidazol-1-yl)methyl]-1-piperidinyl]methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid hydrochloride

A mixture containing4-[(2-nitro-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde (2.0 g,8.4 mM) in dioxane (15 ml) and 1 NHCl (15 ml) was heated at 100° C. for5 hrs. After the reaction, solvent was removed, and the residue,basified with 1N NaOH to pH 10 was extracted with CH₂ Cl₂ (3×30 ml). Theextracts, dried over Na₂ SO₄, were stripped to give a solid (1.7 g, 8mM) which was heated with dimethylformamide dimethylacetal (15 ml) inMeOH--CHCl₃ (4 ml:15 ml) at 100° C. for 10 hrs. The excess ofdimethylformamide dimethylacetal was removed to give4[(2-nitro-1H-imidazol-yl)-methyl]-piperidinecarboxaldehydedimethylacetal. This acetal was added at 0° C. to a mixture of6-aminopenicillanic acid (1.6 g, 7.3 mM) and diisopropylethylamine (1.3ml) in dry chloroform. The reaction was stirred at 0° C. 1 hr and roomtemperature for 3 hrs. After the reaction, solvent was removed in vacuoand dissolved in water (40 ml). The aqueous solution, washed with ethylacetate (2×15 ml), was acidifired to pH 3 and purified on Sephadex LH 20columns to give[2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-[(2-nitro-1H-imidazol-1-yl)methyl]-1-piperidinyl]-methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid as the hydrochloride salt (0.73 g, 21% yield).

EXAMPLE 6[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(2-Amino-1H-imidazol-1-yl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid hydrochloride

The solution of[2S-(2alpha,5alpha,6beta]-3,3-dimethyl-6-[[[4-[(2-nitro-1H-imidazol-1-yl)methyl]-1-piperidinyl]-methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid hydrochloride (0.54 g, 1.1 mM) in water (35 ml) and 0.7 g, 10% byweight of palladium on 90% by weight carbon was hydrogenated (1 atm.)for 1.5 hrs. After the reaction, the catalyst was removed by filtrationand the filtrate was purified on Sephadex LH 20 to give 0.14 g (28%yield) of[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(2-amino-1H-imidazol-1-yl)methyl]-1-piperidinyl]methylene]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid hydrochloride.

EXAMPLE 7 (4-(2-cyanoethyl)-1-piperidinecarboxaldehyde

4-(2-Bromoethyl)-1-piperidinecarboxaldehyde (47 g, 0.213M) and NaCN (24g) in ethanol (470 ml) was refluxed for 4 hours. Solvent was removed,added water (30 ml) and extracted with methylene chloride (4×200 ml).The extracts, dried over NaSO₄, were stripped to dryness and thenpurified on silica gel columns eluted with ethyl acetate to give4-(2-cyanoethyl-1-piperidinecarboxaldehyde (16 g, 50% yield).

EXAMPLE 8 4-[2-(4,5-Dihydro-1H-imidazol-2-yl)ethyl]piperidine

A mixture containing 4-(2-cyanoethyl)-1-piperidinecarboxaldehyde (10 g,0.06M) and ethylenediamine p-toluenesulfonate (30 g, 0.129M) were heatedat 200° C. for 41/2 hours. Crystallization of the crude reaction mixturefrom isopropanol (70 ml) yielded the desired product as thedi-p-toluenesulfonate salt (14 g). The salt was then basified with 2equivalents of MeONa and distilled (0.2 mmHg, 170° C.) to give4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]piperidine (4.1 g, 37% yield).

EXAMPLE 9[2S-(2alpha.5alpha,6beta)]-6-[[[4-[4,5-Dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A mixture containing 4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]piperidine(1 g, 0.0055M), methanol (10 ml) and dimethylformamide dimethylacetal(10 ml) was heated at 90° C. for 8 hours. The excess ofdimethylformamide was removed in vacuo to give4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidine carboxyaldehydedimethylacetal. To the mixture of 6-aminopenicillanic acid (1.01 g,0.0046M) and diisopropylethylamine (0.54 ml) in dried chloroform (30 ml)was added the chloroform solution (20 ml) of the abovepiperidinecarboxaldehyde dimethylacetal at 0° C. The reaction wasstirred at 0° C. for 1 hour and at room temperature for 3 hours. Afterthe reaction, the solvent was removed and the residue dissolved in water(20 ml). The aqueous solution, washed with ethylacetate was acidified topH3 with dil. HCl and purified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylicacid hydrochloride (1.11 g, 45% yield).

EXAMPLE 10 4-(3-Cyanopropyl)-1-piperidinecarboxaldehyde

4-(3-Bromopropyl)-1-piperidinecarboxaldehyde (60 g, 0.256M) and NaCN (25g) in ethanol (600 ml) was refluxed for 7 hours, Solvent was removed,added water (300-400 ml) and extracted with CH₂ Cl₂ (4×200 ml). Theextracts, dried over Na₂ SO₄ was stripped to dryness which was purifiedon silica gel columns, eluted with ethylacetate-hexane (8:2 parts byvolume) to yield 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (28.4 g,61% yield).

EXAMPLE 11 4-[3-(4,5-Dihydro-1H-imidazol-2-yl)propyl]piperidine

To 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (10 g, 0.055M), therewas added ethylenediamine p-toluenesulfonate (30 g, 0.129M) and themixture was heated at 200° C. for 41/2 hours. The reaction mixture wasdissolved in ethanol (100 ml), basified with MeONa (0.26M), filtered andstripped to dryness. The residue was distilled at 170° C., 0.025 mmHg togive 4-[3-(4,5-dihydro-1H-imidazol-2-yl)propyl]piperidine (7.86 g, 72%yield).

EXAMPLE 12[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(4,5-Dihydro-1H-imidazol-2-yl)propyl]-1-piperidinyl]methylene]-amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

By the procedure of the Example 9, the product[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(4,5-dihydro-1H-imidazol-2-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.53 g, 18.5% yield) was obtained from4-[3-(4,5-dihydro-1H-imidazol-2-yl)propyl]piperidine (1.36 g, 0.007M)and 6-aminopenicillanic acid (1.36 g, 0.0063M).

EXAMPLE 134-[3-(2-Ethyl-4-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde

2-Ethyl-4-methyl-1H-imidazole (3.3 g, 30 mM) and sodium hydride (50% byweight in mineral oil, 80 mM) in dimethylformamide (20 ml) was heated at50° C. for 1/2 hour. The solution of4-(3-bromopropyl)-1-piperidinecarboxaldehyde (7 g, 30 mM) indimethylformamide (20 ml) was added at 50° C. and stirred at thattemperature for 4 hours. After the reaction, solvent was removed invacuo and water (100 ml) was added and then extracted with ethyl acetate(2×100 ml). The extracts, dried over Na₂ SO₄, was stripped to drynessand purified on silica gel column, eluted with 2% by volume MeOH, 98% byvolume CH₂ Cl₂, to give4-[3-(2-ethyl-4-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehydeas an oil (4.04 g, 51% yield).

EXAMPLE 14[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-ethyl-4-methyl-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A mixture containing4-[3-(2-Ethyl-4-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde(2 g, 7.5 mM) in dioxane (20 ml) and 1 NHCl (20 ml) was heated at 100°C. for 6 hours. The solvent was then removed and the residue wasbasified with 1N NaOH to pH 10 and then extracted with CH₂ Cl₂ (3×30ml). The combined extracts, dried over NO₂ SO₄, were stripped to drynessto give an oil (1.71 g, 7.2 mM) which was then heated withdimethylformamide dimethylacetal (20 ml) at about 110° C. for 10 hours.The excess of dimethylformamide was removed to give4-[3-(2-ethyl-4-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. This acetal dissolved in chloroform (15ml) was added, at 0° C., to a mixture of 6-aminopenicillanic acid (1.5g, 7 mM) and diisopropylethylamine (1.28 ml). The resulting reactionmixture was stirred at 0° C. for 1 hour and at room temperature for 3hours. After the reaction, the solvent was removed in vacuo and theresidue was dissovled in water (40 ml). The aqueous solution, washedwith ethylacetate was acidified to pH3 with dil. HCl and purified onSephadex columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-ethyl-4-methyl-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (1.18 g, 34% yield).

EXAMPLE 154-[3-(2-Nitro-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde

The mixture of 2-nitroimidazole (11.3 g, 0.1M) and 50% by weight NaH inmineral oil (4.8 g, 0.1M) in dimethylformamide (50 ml) was stirred atroom temperature for 1/2 hr. The solution of4(3-bromo-propyl)-1-piperidine carboxaldehyde (23.4, 0.1M) indimethylformamide (20 ml) was added to the above mixture and heated at110° C. for 15 min. After the reaction, the solvent was removed in vacuowand water (100 ml) was added and the mixture was extracted withethylacetate (72×100 ml). The extracts, dried over Na₂ SO₄, wereconcentrated and purified on silica gel columns, eluted with 5% byvolume MeOH-95% by volume CH₂ Cl₂ to give4-[3-(2-nitro-1H-imidazol-1-yl)propyl]-piperidinecarboxaldehyde (22.8g).

EXAMPLE 16[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-nitro-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride 0.66 molar hydrate

A solution of4-[3-(2-nitro-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde (3.25g, 12.2 mM) in dioxane (90 ml) and 1N HCl (90 ml) was heated at 100° C.for 4 hrs. After the reaction, the solvent was removed in vacuo, and theresidue, basified with 1N NaOH to pH 10, was extracted withmethylenechloride (3×40 ml). The extracts, dried over Na₂ SO₄ werestripped to give an oil (2.62 g, 11 mM). Without further purification,the resulting crude product (2.62 g) and dimethyl formamidedimethylacetal (30 ml) was heated at 100° to about 110° C. for 10 hrs.The excess of dimethyl formamide dimethylacetal was removed at reducedpressure to give 4-[3-(2-nitro-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. This acetal in dry chloroform (30 ml) wasadded at 0° C. to a mixture of 6-aminopenicillanic acid (2.07 g, 9.8 mL)and diisopropylethylamine (1.69 ml). This reaction mixture was stirredat 0° C. for 1 hr. and then at room temperature for 3 hrs. After thisperiod, the solvent was removed in vacuo, the residue was dissolved inwater (50 ml). The resulting aqueous solution, washed with ethylacetate(2×20 ml), was acidified to pH 3 and purified on Sephadex LH 20 columnsto give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-nitro-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride 0.66 molar hydrate (2.3 g, 4.6 mM, 26% yield).

EXAMPLE 17[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-Amino-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

The solution of[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-nitro-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride 0.66 molar hydrate (2.86 g, 5.7 mM) in water (250 ml)and 4.2 g of 10% by weight palladium on 90% by weight charcoal washydrogenated (1 atmosphere pressure) for 1.5 hrs. After the reaction,the catalyst was removed by filtration and the filtrate was freeze-driedto give 1.9 g (4.0 mM, 70% yield) of[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-amino-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride.

EXAMPLE 18 4-[(4,5-Dihydro-1H-Imidazol-2-yl)methyl]piperidine

2-(4-pyridylmethyl)-imidazoline (3.0 g, 0.018M) and platinum oxide (0.3g) in ethanol (50 ml) and 2N HCl (20 ml) was hydrogenated at 45 psig for4 hrs. The catalyst was removed by filtration and the solvent wasstripped. Crystallization from ethanol gave 4.05 g of4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]piperidine as dihydrochloridesalt (89% yield).

EXAMPLE 19[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(4,5-Dihydro-1H-Imidazol-2-yl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A mixture containing the dihydrochloride salt of4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]piperidine (8.5 g, 0.035M) andmethanol (160 ml) which contained sodium methoxide (0.071M) was stirredat room temperature for 10 minutes and dimethylformamide dimethyl acetal(170 ml) was added and heated at 90° C. for 6 hrs. The excess ofdimethylformamide dimethyl acetal was removed to give4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]piperidine carboxaldehydedimethyl acetal. To the mixture of 6-aminopenicillanic acid (6.3 g,0.029M) and diisopropylethylamine (5.1 ml) in dried chloroform was addedthe solution (20 ml CHCl₃ and 5 ml MeOH) of the above piperidinecarboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C.for 1 hr and at room temperature for 3 hrs. After this period, thesolvent was removed in vacuo and dissolved in 150 ml of water. Theaqueous solution, washed with ethyl acetate was acidified to pH 3 withdilute hydrochloric acid and purified on Sephadex LH₂₀ columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (8.1 g, 62% yield).

EXAMPLE 20 4-(1H-Imidazol-2-yl)pyridine

2-(4-pyridyl)-imidazoline (7.0 g, 0.047M) and barium mangnate (52.5 g)in CH₂ Cl₂ (500 ml) were refluxed with stirring for 24 hrs. The reactionmixture was then filtered through diatomaceous earth, washed withmethylene chloride and then ethylacetate. The combined filtrates wereconcentrated and crystallized from ethylacetate-petroleum ether to give4-(1H-imidazol-2-yl)pyridine (4.7 g, 67% yield).

EXAMPLE 21 4-(1H-Imidazol-2-yl)piperidine

4-(1H-imidazol-2-yl)pyridine (4 g, 0.0275M) and platinum oxide (0.5 g)in ethanol (50 ml) and 1N HCl (60 ml) was reduced at 45 psig of hydrogenfor 4 hrs. The reaction mixture was filtered and the filtrate wasconcentrated and crystallized from methanol-ethanol to give the4-(1H-imidazol-2-yl)piperidine as dihydrochloride salt (4.47 g, 88%yield, mp 286°-289°).

EXAMPLE 22[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-Imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride trihydrate

A solution of the dihydrochloride salt of 4-(1H-imidazol-2-yl)piperidine(0.448 g, 0.002M) in methanol (15 ml) which contained sodium methoxide(0.004M) was stirred at room temperature for about 5 minutes anddimethylformamide dimethyl acetal (10 ml) was added and the mixture washeated at 80° C. for 8 hrs. The excess of dimethylformamidedimethylacetal was removed to give 4-(1H-imidazol-2-yl)-1-piperidinecarboxaldehyde dimethylacetal. This acetal was then dissolved in 6 ml ofchloroform. To a mixture of 6-aminopenicillanic acid (0.388 g, 0.0018M)and diisopropylethylamine (0.2 ml) in CHCl₃ (20 ml) was added thechloroform solution of the above piperidine carboxaldehydedimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr androom temperature for 3 hrs. After this period, the solvent was removedand the residue dissolved in water (15 ml). The aqueous solution, washedwith ethylacetate, was acidified to pH 3 with dil. HCl and purified onSephadex LH 20 to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride trihydrate (0.245 g, 26% yield).

EXAMPLE 23 4-(4,5-Dihydro-1H-Imidazol-2-yl)Piperidine

4-(4,5-dihydro-1H-imidazol-2-yl)pyridine (2.4 g, 0.016M) and platinumoxide (0.3 g) in ethanol (36 ml) and 1N HCl (35 ml) were reduced at 45psig of hydrogen for 31/2 hrs. The reaction was filtered and thefiltrate was concentrated and crystallized from ethanol-acetone (4:6parts by volume) to give the 4-(4,5-dihydro-1H-imidazol-2-yl)piperidineas dihydrochloride salt (1.7 g, 44%, mp 119°).

EXAMPLE 24[2S-(2alpha,5alpha,6beta)]-6-[[[4-(4,5-dihydro-1H-imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A solution of the dihydrochloride salt of4-(4,5-dihydro-1H-imidazol-2-yl)piperidine (0.99 g, 0.0044M) in methanol(10 ml) which contained sodium methoxide (0.009M) was stirred at roomtemperature for 10 minutes and dimethylformamide dimethylacetal (10 ml)was added and refluxed at 80° C. for 8 hrs. The excess ofdimethylformamide dimethylacetal was removed to give4-(4,5-dihydro-1H-imidazol-2-yl)-1-piperidinecarboxaldehydedimethylacetal. To a mixture of 6-aminopenicillanic acid (0.785 g,0.0035M) and diisopropyl ethylamine (0.412 ml) in dry chloroform wasadded the chloroform solution (30 ml) of the abovepiperidinecarboxaldehyde dimethyl acetal at 0° C. The reaction wasstirred at 0° C. for 1 hr and at room temperature for 3 hrs. After thisperiod, the solvent was removed in vacuo and the residue was dissolvedin water (40 ml). The aqueous solution washed with ethylacetate wasacidified to pH 3 with dil HCl and purified on Sephadex LH 20 columns togive[2S-(2alpha,5alpha,6beta)]-6-[[[4-(4,5-dihydro-1H-imidazol-2yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.21 g, 11.5% yield).

EXAMPLE 25 4(2-Cyanoethyl)pyridine

A mixture of 3-(4-pyridyl)-propionamide (7.1 g, 0.47M) in POCl₃ (25 ml)was heated at about 100° to about 110° C. for 2 hrs. The excess of POCl₃was removed in vacuo from the reaction. Thereafter water was added andthe resulting solution was basified with aqueous Na₂ CO₃ sol. andextracted with CHCl₃. The combined extracts were dried over Na₂ SO₄ andconcentrated and distilled at 1 mmHg/118°-120° C. to give4(2-cyanoethyl)pyridine as an oil (4.8 g, 77% yield).

EXAMPLE 26 4,5,6,7-Tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine

The mixture of 4-[2-cyanoethyl]pyridine (1.32 g, 0.01M),1,4-diaminobutane (0.88 g, 0.01M) and 1,4-diaminobutanedi-p-toluenesulfonate (4.32 g, 0.01M) was heated at about 190° to about200° C. for 4 hrs. The residue was stirred with ethanol (20 ml) whichcontained EtONa (0.02M) and filtered. The filtrate was concentrated anddistilled at 0.07 mmHg and a temperature of about 180° to about 200° C.to give 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9g, 93% yield).

EXAMPLE 274-[2-(4,5,6,7-Tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine

The 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g,0.009M) and PtO₂ (0.25 g) in ethanol (20 ml) and 2NHCl (15 ml) wasreduced at 45 psig of hydrogen. After the hydrogenation, the solvent wasremoved and the residue was crystallized from ethanol-ether to give 1.5g of 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (60%yield) as dihydrochloride salt.

EXAMPLE 28[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

The dihydrochloride salt of4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]piperidine (1.6 g,5.8 mM) in methanol (12 ml) which contained MeONa (12 mM) anddimethylformamide dimethyl acetal (20 ml) was heated at 90° C. for 8hrs. The excess of dimethylformamide dimethylacetal was removed in vacuoto give the 4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]1-piperidinecarboxaldehyde dimethylacetal. To the mixture of6-aminopenicillanic acid (1.1 g, 5 mM) and diisopropylethylamine (0.96ml) in 20 ml dry CHCl₃ was added the solution (CHCl₃ 8 ml:MeOH 1 ml) ofabove piperidine-carboxaldehyde dimethylacetal at 0° C. The reaction wasstirred at 0° C. for 1 hr and then at room temperature for 3 hrs. Thesolvent was then removed, and water added (30 ml). The aqueous solution,washed with ethylacetate, was acidified to pH 3 with dilute aqueous HCland purified on Sephadex LH 20 column to yield[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.85 g, 38% yield)

EXAMPLE 29 3-(1H-Imidazol-2-yl)pyridine

2-(3-pyridyl)imidazoline (7.2 g, 0.049M), and barium manganate (52.5 g)in CH₂ Cl₂ (500 ml) were refluxed for 24 hrs. The reaction mixture wasthen filtered through diatomaceous earth, washed with ethylacetate(3×200 ml) and methanol (3×100 ml). The combined filtrates wereconcentrated to yield an oil which was purified on silica gel column,eluted with 20% by volume methanol 80% by volume methylene dichloride,to give 3-(1H-imidazol-2-yl)pyridine (4.66 g, 64.7%).

EXAMPLE 30 3-(1H-Imidazol-2-yl)piperidine

3-(1H-imidazol-2-yl)pyridine (4.0 g, 0.0275M) and platinum oxide (0.5 g)in ethyl alcohol (50 ml) and 1NHCl (50 ml) was reduced at 45 psig ofhydrogen for 4 hrs. The reaction mixture was filtered and the filtratewas stripped to dryness and crystallized from MeOH-EtOH to give3-(1H-imidazol-2-yl)piperidine (4.5 g, 74% yield, mp 295° dec.).

EXAMPLE 31[2S-(2alpha,5alpha,6beta)]-6-[[[3-(1H-Imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A mixture containing the dihydrochloride salt of3-(1H-imidazol-2-yl)piperidine (0.99 g, 0.0044M) and methanol (10 ml)which contained sodium methoxide (0.009M) was stirred at roomtemperature for 10 min. and dimethylformamide dimethylacetal (10 ml) wasadded and heated at 90° C. for 8 hrs. The excess of dimethylformamidedimethylacetal was removed to give3-(1H-imidazol-2-yl)-1-piperidinecarboxaldehyde dimethylacetal. To themixture of 6-aminopenicillanic acid (0.77 g, 0.0035M) and diisopropylethylamine (0.42 ml) in CHCl₃ (30 ml) was added the chloroform solution(30 ml) of the above piperidine carboxaldehyde dimethylacetal at 0° C.The reaction was stirred at 0° C. for 1 hr and then at room temperaturefor 3 hrs. After this period, the solvent was removed and the residuedissolved in water (30 ml). The aqueous solution, washed withethylacetate, was acidified to pH 3 with dilute aqueous HCl and purifiedon Sephadex LH20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[3-(1H-imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.52 g, 28.8% yield).

EXAMPLE 32 4[3-(1H-Imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde

The mixture of imidazole (0.7 g, 0.01M) and NaH (50% by weight inmineral oil, 0.9 g, 0.018M) in dimethylformamide (60 ml) was heated at50° C. for 1/2 hr. and 4-(3-bromopropyl)-1-piperidinecarboxaldehyde(2.93 g, 0.0125M) in dimethylformamide (20 ml) was added. The reactionwas heated at 50° C. for 4 hrs. After the reaction, the solvent wasremoved in vacuo, water was added and the product was extracted with CH₂Cl₂ (3×50 ml). The combined extracts, dried over Na₂ SO₄, were strippedto dryness and purified on silica gel column eluted with 10% by volumemethanol-90% by volume methylenechloride to give4[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde as an oil (2.12g, 96%).

EXAMPLE 33 4-[3-(1H-Imidazol-1-yl)propyl]-piperidine

A mixture of 4[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde(2.12 g, 0.0095M) in dioxane (80 ml) and 2NHCl (11 ml) was refluxed for51/2 hrs. After the reaction, the solvent was removed, water was addedand the solution was basified with 2N NaOH to pH 10 and extracted withCH₂ Cl₂ (3×50 ml). The extracts were concentrated to give an oil (1.55g, 80%). The dihydrochloride salt of the4[3-(1H-imidazol-1-yl)propyl]-piperidine which was crystallized fromacetone has m.p. 184°-186° C.

EXAMPLE 34[2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1H-Imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.2 mole hydrochloride monohydrate

A mixture of 4-[3-(1H-imidazol-1-yl)propyl]-piperidine (1.5 g, 0.0078M)and dimethylformamide dimethylacetal (10 ml) was heated at 100° C. for16 hrs. The excess of dimethylformamide dimethylacetal was removed togive 4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehydedimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g,0.0053M) and diisopropylethylamine (1.03 ml) in dry CHCl₃ (9 ml) wasadded the above piperidinecarboxaldehyde in CHCl₃ (5 ml) at 0° C. andstirred at that temperature for 1 hr, then at room temperature for 3hrs. After the reaction, the solvent was removed and the residuedissolved in water (40 ml). The aqueous solution, washed with diethylether, was adjusted to pH 3 with dilute aqueous HCl and purified onSephadex LH 20 column to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.2 mole hydrochloride monohydrate (0.87 g, 39% yield).

EXAMPLE 35 2-(4-Pyridylmethyl)-imidazole

The mixture of 2-(4-pyridylmethyl)-imidazoline (6.6 g, 0.04M) andRaney-Nickle (3 g) was heated initially at 210° C. and gradually raisedto 250° C. in 15 min. After the reaction, the reaction was dissolved inethanol (50 ml) and filtered to remove the catalyst. The filtrate wasstripped to dryness and distilled (0.25 mmHg, 180° C.) to give2-(4-pyridylmethyl)-imidazole (4.1 g, 62% yield).

EXAMPLE 36 4-(1H-Imidazol-2-yl-methyl)-piperidine

2-(4-pyridylmethyl)imidazole (4 g, 0.025M) and platinum oxide (0.4 g) inethanol (40 ml) and 2NHCl (50 ml) was hydrogenated at 45 psig for 4 hrs.The catalyst was removed by filtration and the filtrate was stripped todryness. Crystallization from ethanol gave4-(1H-imidazol-2-yl-methyl)piperidine as the dihydrochloride salt m.p.251°-252° C. (5.2 g, 87% yield). The mixture of2-(4-pyridylmethyl)-imidazole (2.38 g, 10 mM) and NaOCH₃ (10 mM) inmethanol (20 ml) was stirred for 10 min. and filtered. The filtrate wasstripped to dryness and distilled from about 180° to about 200° C./0.3mmHg to give the free base of 4-(1H-imidazol-2-yl-methyl)piperidine.

EXAMPLE 37[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-2-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride

The free base of 4-(1H-imidazol-2-yl-methyl)piperidine (1.0 g, 0.006M)and dimethylformamide dimethylacetal (15 ml) in methanol (20 ml) wereheated at 90° C. for 8 hrs. The excess of dimethylformamidedimethylacetal was removed at the reduced pressure to give4-(1H-imidazol-2-yl-methyl)piperidine carboxaldehyde dimethylacetal. Tothe mixture of 6-aminopenicillanic acid (1.16 g, 0.0054M) anddiisopropyl ethylamine (0.96 ml) in dry chloroform (20 ml) was added thesolution (10 ml CHCl₃ and 2 ml MeOH) of the above piperidinecarboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C.for 1 hr. and then at room temperature for 3 hrs. After this period, thesolvent was removed in vacuo and the residue dissolved in water (20 ml).The aqueous solution, washed with ethylacetate was acidified to pH 3with dilute aqueous HCl and purified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-(1H-imidazol-2-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.84 g, 33%).

EXAMPLE 384-[(2-Triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde

A mixture of 2-triphenylmethylimidazole (0.34 g, 0.001M) and sodiumhydride (0.057 g, 50% by weight in mineral oil, 0.0024M) indimethylformamide (10 ml) was stirred at room temperature for 1/2 hr andheated to 50° C. To the above mixture, a solution of4-bromomethyl-1-piperidinecarboxaldehyde (0.47 g, 0.001M) indimethylformamide (2 ml) was added and the reaction was continued bymaintaining heating at 50° C. for 4 hrs. After the reaction, solvent wasremoved in vacuo and water (20 ml) was added. The mixture was extractedwith ethylacetate and the extracts, dried over sodium sulfate, werestripped to dryness. Purification on preparative thin layerchromatography plates, eluting with 5% by volume of methanol in 95% byvolume chloroform gave4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde(0.176 g, 37.6% yield).

EXAMPLE 394-[(2-Triphenylmethylaminomethyl-1H-Imidazol-1-yl)methyl]-piperidine

A mixture of4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde(0.48 g, 0.00103M), 2N sodium hydroxide (24 ml) and methanol (24 ml) washeated at 50° C. for 4 hrs. The reaction was concentrated to about 20 mlat room temperature and extracted with ethylacetate. Th extracts, driedover sodium sulfate, was stripped to dryness and purified on preparativethin layer chromatography plates to give4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidine(0.167 g, 37% yield).

EXAMPLE 40[2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(Aminomethyl)-1H-imidazol-1-yl]methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane2-carboxylic acid hydrochloride

A mixture of4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]piperidine(1.45 g, 0.0033M) and dimethylformamide dimethylacetal wass heated at100° C. for 8 hrs. After this period, the reaction was stripped todryness to give4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidinecarboxaldehyde dimethylacetal. The solution of thepiperidinecarboxaldehydedimethylacetal in methylene chloride (5 ml) wasadded to the mixture of 6-aminopenicillanic acid (0.57 g, 0.0026M) anddiisopropylethylamine (0.45 ml) in methylene chloride (5 ml) at 0° C.and stirred at room temperature for 3 hrs. The solvent was removed andthe residue was stirred for 2 hrs in water (20 ml) which was maintainedat pH 3 with 1NHCl. The mixture was filtered and the filtrate waspurified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(aminomethyl)-1H-imidazol-1-yl]methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.27 g, 24% yield).

EXAMPLE 41 1-[3-(4-Piperidinyl)propyl]-1H-imidazole-2-amine

A mixture of4[3-(2-carbobenzyloxyamino-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde(2.3 g, 0.0062M) in dioxane (360 ml) and 0.5NHCl (25 ml) was heated toreflux for 5 hrs. After the reaction, the solvent was removed andcrystallized in ethanol to give1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-amine as the dihydrochloridesalt mp 220°-1° C. (1.075 g, 82% yield). This dihydrochloride salt(1.075 g) was converted to the free base (0.5 g, 39% yield) by passingthrough basic ion-exchange resin (AGT-1-X4) and eluted with water.

EXAMPLE 42[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-[2-[[(dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.7 molar hydrochloride 2.6 molar hydrate

A mixture of 1-[3(4-piperidinyl)propyl]-1H-imidazole-2-amine (0.5 g,0.0024M) and dimethylformamide dimethylacetal (7 ml) was heated at 100°C. for 10 hrs. The reaction was then stripped to dryness to give4-[3-(2[[[dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinecarboxaldehydedimethylacetal. The solution of the piperidinecarboxaldehydedimethylacetal in chloroform (4 ml) was added to the mixture of6-aminopenicillanic acid (0.46 g, 0.0216M) and diisopropylethylamine(0.37 ml) in chloroform (10 ml) at 0° C. and then stirred at roomtemperature for 31/2 hrs. After this period, the solvent was removed andwater (20 ml) was added. The aqueous solution, after being washed withethylacetate, was acidified from about pH 3 to about 3.5 and purified onSephadex L-20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-[2-[[(dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.7 molar hydrochloride 2.6 molar hydrate (0.64 g, 64% yield).

EXAMPLE 43 4-[2-(1-Ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine

A mixture of 4-(2-cyanoethyl)pyridine (1.32 g, 0.01M) andN-ethyl-1,2-diaminoethane mono-p-toluenesulfonate (5.5 g, 0.02M) wereheated at 190° C. for 4 hrs under nitrogen. The reaction mixture wasdissolved in ethanol (30 ml) and sodium ethoxide (0.02M) in ethanol (50ml) was added. The mixture was filtered and the filtrate was stripped todryness and distilled at 130° C./0.2 mmHg to yield4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.2 g, 60%yield).

EXAMPLE 44 4-[2-(1-Ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine

The solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine(1.1 g, 0.0054M) in ethanol (15 ml) and water (15 ml) was added con.HCl(3 ml) and platinum oxide (0.2 g). The mixture was hydrogenated at 45psig for 4 hrs. The catalyst was removed by filtration and the filtratewas stripped to dryness in vacuo. The residue was dissolved in methanol(25 ml) and sodium methoxide (0.011M) was added and filtered. Thefiltrate was stripped to dryness and distilled at about 150° to about175° C./0.2 mm Hg to yield4-[2-(1-ethyl-4,5-dihydro-imdazol-2-yl)ethyl]piperidine as an oil (0.8g, 70% yield).

EXAMPLE 45[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride

A solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]piperidine(0.66 g, 0.0031M) in methanol (6 ml) and dimethylformamidedimethylacetal (6 ml) was heated at 90° C. for 6 hrs. Removal of theexcess of dimethylformamide dimethylacetal gave4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-1-piperidinecarboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehyde dimethylacetal in chloroform (5 ml) was then added to amixture of 6-aminopenicillanic acid (0.6 g, 0.0028M) anddiisopropylethylamine (0.5 ml) in chloroform (6 ml) at 0° C. Thereaction was stirred at 0° C. for 1 hr and room temperature for 3 hrs.The solvent was removed and water (10 ml) was added. After being washedwith ethylacetate, the aqueous solution, acidified from about pH 3 toabout 3.5 was purified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(1-ethyl-4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.46 g, 35% yield).

EXAMPLE 46 1,4,5,6-Tetrahydro-2-[(4-piperidinyl)methyl]-pyrimidine

A mixture of 4-cyanomethyl piperidine-1-carboxaldehyde (4. g, 0.026M)and 1,3-diaminopropane mono p-toluenesulfonate (7.3 g, 0.052M) washeated at 100° C. for 1/2 hrs and 200° C. for 2 hrs. The reactionmixture was dissolved in ethanol (50 ml) and sodium ethoxide (0.052M)was added. The mixture was filtered and the filtrate was stripped todryness and distilled from about 170° to about 190° C./0.2 mmHg to yield1,4,5,6-tetrahydro-2-[(4-piperidinyl)methyl]-pyrimidine (2.7 g, 56.7%yield). This compound was characterized as dihydrochloride salt, mp279°-281° C. (EtOH).

EXAMPLE 47[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(1,4,5,6-tetrahydro-2-pyrimidinyl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A solution of 1,4,5,6-tetrahydro-2-[(4-piperidinyl)methyl]-pyrimidine(0.9 g, 0.005M) in methanol (5 ml) and dimethylformamidedimethylacetal(15 ml) was heated at 90° C. for 8 hrs. The reaction was then strippedto dryness to yield4-[(1,4,5,6-tetrahydro-2-pyrimidyl)methyl]-1-piperidinecarboxaldehydedimethylacetal. The solution of the piperidine carboxaldehydedimethylacetal in methylene chloride (5 ml) was added to a mixture of6-aminopenicillanic acid (0.97 g, 0.0045M) and diisopropylethylamine(0.76 ml) in methylene chloride (10 ml) at 0° C. The reaction wasstirred at 0° C. for 1 hr and room temperature for 3 hrs. The solventwas removed and water (20 ml) was added. After being washed with ethylacetate, the aqueous solution, acidified to pH 3 to about 3.5, waspurified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(1,4,5,6-tetrahydro-2-pyrimidinyl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (0.14 g, 7% yield).

EXAMPLE 48 1-[3-(4-Piperidinyl)propyl]-1H-imidazole-2-carboxylic acid1.75 molar hydrochloride 0.65 molar hydrate

The solution of4-[3-(2-hydroxymethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde in acetone (63 ml) was cooled to 0° C. and potassiumpermanganate (5.5 g, 0.035M) was added portionwise. After completeaddition, the reaction was stirred at 0° C. for 2 hrs. The acetonesolution was separated by filtration, and the residue was stirred twicewith water (50 ml). The aqueous solution was freeze dried to yield4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde(5.5 g, 83% yield). This product (7.1 g, 0.027M) in water (26 ml) and 1NNaOH (26 ml) was heated at 100° C. for 5 hrs. The reaction was adjustedpH 6 and purified on ion-exchange column (Bio-Rex 70) eluted with 0.01N,0.02N, 0.04N, 0.08N and 0.1N HCl solution successively to give 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molarhydrochloride 0.65 molar hydrate (4.6 g, 73% yield).

EXAMPLE 49[2S-(2alpha,5alpha,6beta]-6-[[[1-(3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate

A mixture of 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid1.75 molar hydrochloride 0.65 molar hydrate (1.3 g, 0.0047M) and sodiummethoxide (0.005M) in methanol (23 ml) was added to dimethylformamidedimethylacetal (15 ml) and heated at 80° C. for 8 hrs. The reactionmixture was filtered and stripped to dryness to give4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde.The solution of the above piperidine carboxaldehyde dimethylacetal inmethanol (5 ml) was then added to a mixture of 6-aminopenicillanic acid(0.81 g, 0.0037M) and diisopropylethylamine (0.4 ml) in chloroform (30ml) at 0° C. The reaction was stirred at 0° C. 2 hrs and roomtemperature for 2 hrs. The solvent was removed and water (15 ml) wasadded. After being washed with ether, the aqueous solution, acidified topH 3 to about 3.5, was purified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta]-6-[[[1-(3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate (0.38 g, 17% yield).

EXAMPLE 504-[3-(1H-2-Hydroxymethyl-imidazol-1-yl)propyl]-1-piperidine-carboxaldehyde

4-[3(1H-imidazol-1-yl)propyl)]-1-piperidinecarboxaldehyde (22 g, 0.1M)and 37% by weight aqueous formaldehyde (25.4 g) were heated at 140° C.in autoclave for 5 hrs. After the reaction, the solvent was removed andthe residue purified on silica gel, eluted with 5% by volume MeOH--CHCl₃95% by volume then 10% by volume MeOH-90% by volume CHCl₃ to give4-[3-(1H-2-hydroxymethyl-imidzol-1-yl)propyl]-1-piperidinecarboxaldehyde (10 g, 40% yield).

EXAMPLE 51 4-[3-(1H-3-Hydroxymethyl-imidazol-1-yl)propyl]piperidine

A mixture of4-[3-(1H-2-hydroxymethyl-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde(1.5 g, 0.0059M) in dioxane (45 ml) and 0.5N HCl (45 ml) were heated andrefluxed for 4 hrs. After the reaction, the mixture was stripped todryness to yield 1.5 g of4-[3(1H-2-hydroxymethyl-imidazol-1-yl)propyl]piperidine as HCl salt(m.p. 180°-184°, 98% by weight yield). The HCl salt of4-[3-(1H-2-hydroxymethylimidazol-1-yl)propyl]piperidine was passedthrough a basic ion-exchange resin (AG-1-4X) to give4-[3-(1H-2-hydroxymethyl-imidazol-1-yl)propyl]piperidine as free base(1.4 g).

EXAMPLE 52[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-[2-(hydroxymethyl)-1H-imidazol-1-yl]propyl-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[4.2.0]heptane-2-carboxylicacid hydrochloride 1.1 molar hydrate

A mixture of 4-[3-(1H-2-hydroxymethyl-imidazol-1-yl)propyl]piperidine(0.3 g, 0.0013M) and dimethylformamide dimethylacetal (10 ml) was heatedat 80° C. for 8 hrs. After the reaction, the mixture was stripped todryness and methanol (2 ml) was added and heated for 10 min. at 100° C.The solvent was removed in vacuo to give4-[3-(1H-2-hydroxymethyl-imidazol-1-yl)propyl]-1-piperidinecarboxaldehydedimethylacetal. The solution of the above piperidine carboxaldehydedimethylacetal in chloroform (5 ml) was then added to a mixture of6-aminopenicillanic acid (0.289 g, 0.0013M) and diisopropylethylamine(0.24 ml) in chloroform (10 ml) at 0° C. The reaction was stirred at 0°C. for 1 hr and room temperature for 3 hrs. The solvent was removed andwater (10 ml) was added. After being washed with diethyl ether, theaqueous solution, acidified to a pH 3 to about 3.5 was purified onSephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-[2-hydroxymethyl)-1H-imidazol-1-yl]propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[4.2.0]heptane-2-carboxylicacid hydrochloride 1.1 molar hydrate (0.094 g, 14% yield).

EXAMPLE 53 4-[3-(2,4,5-Trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde

A mixture of trimethyloxazole (10.18 g, 0.091M),4[3-aminopropyl]-1-piperidinecarboxaldehyde and acetic acid (0.16 g)were heated at 145° C. for 6 hrs. After the reaction, the excess oftrimethyl oxazole was removed at reduced pressure and the residue waspurified on silica gel column eluted with 4 to 10% of methanol by volumein CHCl₃ to yield4-[3-(2,4,5,-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehydeas an oil (3.3 g, 50% yield).

EXAMPLE 54 4-[3-(2,4,5-Trimethyl-1H-imidazol-1-yl)propyl]-1-piperidine

A solution of4-[3-(2,4,5-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde(0.84 g, 0.0032M) in 1N HCl (20 ml) and dioxane (20 ml) was heated at100° C. for 4 hrs. After the reaction, the solvent was removed and tothe residue there was added 1N NaOH (20 ml). The resulting mixture wasextracted with chloroform (30 ml×3). The combined extract, dried oversodium sulfate, were stripped to dryness to yield4-[3-(2,4,5,-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidine (0.75 g).

EXAMPLE 55[2S-(2alpha,5alpha,6beta)]-6[[4-[3-[(2,4,5-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate hydrochloride

A mixture of 4-[3-(2,4,5-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidine(0.75 g, 0.0032M) and dimethylformamide dimethylacetal (20 ml) washeated at 100° C. for 9 hrs. The reaction was stripped to dryness toyield4-[3-(2,4,5-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehydedimethylacetal. The solution of the above piperidine carboxaldehydedimethylacetal in chloroform (4 ml) was then added to a mixture of6-aminopenicillanic acid (0.67 g, 0.003M) and diisopropylethylamine(0.47 ml) in chloroform (12 ml) at 0° C. The reaction was stirred at 0°C. for 1 hr and room temperature for 3 hrs. Solvent was removed andwater (15 ml) was added. After being washed with diethyl ether, theaqueous solution, acidified to a pH 3 to about 3.5, was purified onSephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6[[4-[3-[(2,4,5-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate hydrochloride (0.71 g, 46% yield).

EXAMPLE 56 4-(Bromomethyl)-1-piperidinecarboxaldehyde

A one-liter, three-necked flask equipped with a mechanical stirrer,dropping funnel, and nitrogen bubbler was charged with 20 g (0.155 mol)of isonipecotic acid and 140 mL of tetrahydrofuran. The flask was cooledin an ice bath and 233 mL of (1M) diborane/THF was added dropwise. Thebath was removed, the reaction stirred two hours at room temperature andthen heated for six hours in an 80° bath. The flask was cooled in an icebath and 140 mL of methyl alcohol added dropwise. The resulting solutionwas stripped to dryness and 200 mL of absolute alcohol was addedfollowed by slow addition of 50 mL of 10% by weight of anhydrous HCl inabsolute alcohol. This alcoholic solution was heated at 21/2-3 hours atreflux. The reaction was then stripped to dryness and traces of waterremoved by azeotropic distillation with benzene on the rotaryevaporator. The azeotroping procedure was repeated followed by drying invacuo at room temperature. The crude hydrochloride was used in the nextstep.

The flask containing the above material was equipped with a mechanicalstirrer, dropping funnel, condenser, and nitrogen bubbler, placed in a55° bath and 25 mL of phosphorous tribromide was added dropwise. ThenHBr fumes came through the bubbler, the bath was removed and additionwas continued. The heating was continued after addition and continued at100° for 90 minutes. The reaction was cooled to 25° and anhydrous etheradded to convert the reaction product into a granular solid withvigorous stirring. The solid was filtered under nitrogen to give 45.6 gof crude hydrobromide salt.

A two liter, three-necked flask equipped with a mechanical stirrer,dropping funnel, nitrogen bubbler and thermometer was charged with 45.6g of 4-(bromomethyl)piperidine hydrobromide, 300 mL of tetrahydrofuranand 300 mL of dimethylformamide and cooled to 0°. To the cooled solutionwas added 27.2 mL of acetic formic anhydride below 5°. When the additionwas completed, 54.4 mL of triethylamine was added dropwise between 0°and 5°. The cooling bath was removed and the reaction stirred overnightat room temperature. The salts were removed by filtration and thesolvent removed in vacuo to yield a yellow oil. The oil was treated with100 mL of brine and then extracted with three 100 mL portions of diethylether. The ether was dried over anhydrous sodium sulfate. Removal of theether afforded 24.6 g of light yellow oil. The crude oil was purified byhigh pressure liquid chromatography using two columns. Removal of thesolvent from the desired fractions gave 18.0 g (56.7% yield) of4-(bromomethyl)-1-piperidinecarboxaldehyde.

EXAMPLE 57 4-[(1H-Imidazol-1-yl)methyl]-piperidine

To a mixture of sodium hydride (5.04 g, 50% by weight in mineral oil,0.105M) in dimethylformamide (50 ml) was added the solution of imidazole(7.13 g, 0.104M) in dimethylformamide (100 ml) at room temperature andthen stirred for additional 1/2 hr. The reaction was then heated at 50°C. and the solution of 4-(bromomethyl)-1-piperidine carboxaldehyde (18g, 0.087M) in dimethylformamide (100 ml) was added slowly. After theaddition, the reaction mixture heating was continued at 50° C. for 4hrs. The solvent was removed in vacuo, water (about 200 ml) was added tothe residue and the mixture was extracted with methylene chloride. Thecombined extracts, dried over sodium sulfate, was stripped to dryness togive the crude product (12 g) which was purified on silica gel columneluted with methanol-chloroform (1:9 v/v) to give 7.3 g of4[1H-imidazol-1-yl)methyl]-1-piperidinecarboxaldehyde. Thepiperidinecarboxaldehyde (7.3) in 2N HCl (100 ml) and dioxane (100 ml)was heated at 100° C. for 51/2 hr. After the reaction, solvent wasremoved and the residue, dissolved in water (100 ml), was basified with4N NaOH to pH 11 and extracted with methylene chloride. The combinedextracts, dried over sodium sulfate, were stripped to dryness to yield6.0 g of 4-[(1H-imidazol-1-yl)methyl]-piperidine (40% yield).

EXAMPLE 58[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-Imidazol-1-yl-methyl)-1-piperidinyl]methylene]amino-3,3-dimethyl-6-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid

A mixture of 4-[(1H-imidazol-1-yl)methyl]-piperidine (5 g, 0.03M) anddimethylformamide dimethylacetal (40 ml) was heated at 100° C. for 8hrs. Removal of the excess of dimethylformamide dimethylacetal gave4-[(imidazol-1-yl)methyl]-1-piperidine carboxaldehyde dimethylacetal(6.33 g) which was dissolved in methylene chloride (25 ml) and added tothe mixture of 6-aminopenicillanic acid (5.15 g, 0.024M) anddiisopropylethylamine (3.14 ml) in methylene chloride (90 ml) at 0° C.The reaction was stirred at 0° C. for 1 hr and room temperature for 3hrs. The solvent was then removed and water (80 ml) was added. Afterbeing washed with ethylacetate, the aqueous solution, acidified to pH 3,was purified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-1-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-6-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (5.2 g, 55%yield).

EXAMPLE 594-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-1-piperidinecarboxaldehyde

A mixture of 2-methylimidazole (2 g, 0.025M) and sodium hydride (1.2 g,50% in mineral oil, 0.025M) in dimethylformamide (20 ml) was stirred atroom temperature for 1/2 hr. The reaction mixture was then heated at 50°C. and the solution of 4(3-bromopropyl)piperidine carboxaldehyde (4.6 g,0.02M) in dimethylformamide (20 ml) was added slowly. After completingthe addition, the reaction was heated at 50° C. for 4 hrs and thensolvent was removed in vacuo. Water (80 ml) was added to the residue andthe mixture was extracted with methylene chloride. The combinedextracts, dried over sodium sulfate, were stripped to dryness to yieldan oil. The oil was purified on silica gel column, eluted with methanolchloroform (1:9 v/v) to give4-[3-(2-methyl-1H-imidazol-1-yl)-propyl]-1-piperidinecarboxaldehyde(3.86 g, 88% yield).

EXAMPLE 60 4-[3-(2-Methyl-1H-imidazol-1-yl)propyl]piperidine

A mixture of4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde (3.8g, 0.016M) in dioxane (100 ml) and 2N HCl (25 ml) was heated andrefluxed for 51/2 hrs. After this period, solvent was removed, and 1NNaOH (50 ml) was added to the residue. This mixture was then extractedwith methylene chloride (5×50 ml). The combined extracts, dried oversodium sulfate, were stripped to dryness to yield4-[3-(2-methyl-1H-imidazol-1-yl)propyl]piperidine (2.3 g, 65% yield).

EXAMPLE 61[2S-(2alpha,5alpha,6beta)]-3,3-Dimethyl-6-[[[4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.15 molar hydrochloride 1.75 molar hydrate

A mixture of 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]piperidine (2.3 g,0.0105M) and dimethylformamide dimethylacetal (20 ml) was heated at 100°C. for 6 hrs. Removal of the excess of dimethylformamide dimethylacetalgave 4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehydedimethylacetal. A solution of this piperidine carboxaldehydedimethylacetal in methylene chloride (10 ml) was added to a mixture of6-aminopenicillanic acid (2.16, 0.01M) and diisopropyl ethylamine (1.15ml) in methylene chloride (50 ml) at 0° C. The reaction was stirred at0° C. for 1 hr and room temperature for 3 hrs. The solvent was removedand water (50 ml) was added. After being washed with ether, the aqueoussolution, acidified to pH 3, was purified on Sephadex LH 20 columns togive[2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.15 molar hydrochloride 1.75 molar hydrate (1.76 g, 33% yield).

EXAMPLE 62Hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine-carboxaldehyde

To a mixture of sodium hydride (3.4 g, 50% by weight in mineral oil,0.071M) in dimethylformamide (50 ml) was added the solution of imidazole(4.8 g, 0.071M) in dimethylformamide (100 ml) and the reaction wasstirred at room temperature for 1/2 hrs then heated to 50° C. To theabove reaction mixture, a solution ofhexahydro-4-bromo-1H-azepinecarboxaldehyde (13.9 g, 0.059M) in dimethylformamide (150 ml) was added slowly at 50° C. and continued to stir atthat temperature for 21/2 hrs the solvent was removed in vacuo, water(300 ml) was added and the mixture was extracted with ethylacetate(4×200 ml). The combined extracts, dried over sodium sulfate, werestripped to dryness and purified on silica gel, eluted with 2% by volumeof methanol in methylene chloride to yieldhexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepinecarboxaldehyde (12 g,90% yield).

EXAMPLE 63 Hexahydro-4-[ 2-(1H-imidazol-1-yl)ethyl]-1H-azepine

A mixture ofhexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine-carboxaldehyde (11 g,0.05M) in dioxane (1.65 ml) and 2N HCl (82 ml) was heated and refluxedfor 15 hrs. The solvent was removed, water (100 ml) was added and theresulting mixture was washed with methylene chloride (3×20 ml). Afterwashing, the aqueous solution was basified with 4N NaOH to pH 12 andextracted with methylene chloride (4×75 ml). The combined extracts,dried over sodium sulfate, were stripped to yieldhexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine as an oil (6 g, 62%yield). This compound was characterized as dihydrochloride salt m.p.176°-177° C.

EXAMPLE 64[2S-(2alpha,5alpha,6beta)]-6-[[4-[Hexahydro[2-(1H-imidazol-1-yl)ethyl]-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.2 molar hydrochloride hydrate (diastereomers)

A mixture of hexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine (6.0 g,0.031M) and dimethylformamide dimethylacetal (33 ml) was heated at 100°C. for 4 hrs. The reaction was stripped to dryness to givehexahydro-4-[2-(1H-imidazol-1-yl)ethyl]-1H-azepine carboxaldehydedimethylacetal. The solution of the hexahydroazepine carboxaldehydedimethylacetal in methylene chloride (40 ml) was added to the mixture of6-aminopenicillanic acid (5.7 g, 0.026M) and diisopropylethylamine (3.15ml) in methylene chloride (150 ml) at 0° C. and stirred at 0° C. for 1hr, room temperature for 3 hrs. The solvent was removed and water (100ml) was added. After being washed with ether, the aqueous solution,acidified to pH 3, was purified on Sephadex LH 20 columns to give[2S-(2alpha,5alpha,6beta)]-6-[[4-[hexahydro[2-(1H-imidazol-1-yl)ethyl]-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.2 molar hydrochloride hydrate (diastereomers) (4.0 g, 32% yield).

EXAMPLE 654-[(4,5-Dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl]-piperidine

A mixture containing 4(cyanomethyl)-1-piperidinecarboxaldehyde (3.5 g,0.023M) and 1,2-diamino-2-methylpropane mono-p-toluenesulfonate (12.4 g,0.047M) was heated at 185° C. under nitrogen for 5 hrs. The reactionmixture was dissolved in ethanol (20 ml), basified with sodium ethoxide(0.052M), filtered and stripped to dryness. The residue was distilled at150° C. to about 185° C., 0.02 mmHg, to give (3.1 g, 63%)4-[(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl]-piperidine.

EXAMPLE 66[2S-(2alpha,5alpha,6beta)]-6-[[[4-(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl]-1-piperidinyl]methylene]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

By the procedure of Example 9, the product[2S-(2alpha,5alpha,6beta)]-6-[[[4-(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl[-1-piperidinyl]methylene]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride (1.2 g, 48% yield) was obtained from4-[(4,5-dihydro-5,5-dimethyl-1H-imidazol-2-yl)methyl]-piperidine (1.4 g,0.0068M) and 6-aminopenicillanic acid (1.1 g, 0.0055M).

EXAMPLE 67rac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine

A mixture containing 2-cyanoethyl hexahydro-1H-azepine-1-carboxaldehyde(1.94 g, 0.01M) and ethylenediamine p-toluenesulfonate (5.4 g, 0.023M)was heated at 200° C. under nitrogen for 41/2 hrs. The mixture wasdissolved in ethanol (30 ml), basified with sodium ethoxide (0.024M),filtered and stripped to dryness. The residue was distilled at 180° toabout 190° C., 0.05 mmHg to giverac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine (79%yield).

EXAMPLE 68[2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepin-1-yl]-methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

A mixture containingrac-4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine (1.95g, 0.01M), methanol (50 ml) and dimethylformamide dimethylacetal (36 ml)was heated at 90° C. for 8 hrs. The excess of dimethylformamidedimethylacetal was removed in vacuo to give4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepine-1-carboxaldehydedimethylacetal to the mixture of 6-aminopenicillanic acid (1.95 g,0.009M) and diisopropylethylamine (1.52 ml) in dry chloroform (25 ml)was added the solution fo the above hexahydroazepine carboxaldehydedimethylacetal in dry chloroform (10 ml) at 0° C. The reaction wasstirred at 0° C. for 1 hr. and at room temperature for 3 hrs. After thereaction solvent was removed and the residue dissolved in water (30 ml).The aqueous solution, washed with ethylacetate was acidified to pH 3with dil. HCl and purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]hexahydro-1H-azepin-1-yl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hyrochloride (1.03 g, 27% yield).

EXAMPLE 69

The in vitro antibacterial activity of the following compounds:

Compound

A:[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-1-yl-methyl)-1-piperidinyl]methylene]amino-3,3-dimethyl-6-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid

B:[2S-2alpha,5alpha,6beta)]-6-[[[4-[2-(1H-imidazol-1-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate hydrochloride

C:[2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.2 mole hydrochloride monohydrate

D:[2S-(2alpha,5alpha,6beta)]-6-[[4-[hexahydro[2-(1H-imidazol-1-yl)ethyl]-1H-azepin-1-yl]methylene]amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.2 molar hydrochloride hydrate (diastereomers)

E:[2S-(2alpha,5alpha,6beta)]-6[[4-[3-[(2,4,5-trimethyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrate hydrochloride

F:[2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-[3-(2-methyl-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.15 molar hydrochloride 1.75 molar hydrate

G:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-ethyl-4methyl-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

H:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(2-amino-1H-imidazol-1-yl)methyl-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

I:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-amino-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hpetane-2-carboxylicacid hydrochloride

J:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(aminomethyl)-1H-imidazol-1-yl]methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

K:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-(2-nitro-1H-imidazol-1-yl)propyl]piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride 0.66 molar hydrate

L:[2S-(2alpha,5alpha,6beta)]-6-[[[4-(4,5-dihydro-1H-imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

M:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

N:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

O:[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-2-yl-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride trihydrate

P:[2S-(2alpha,5alpha,6beta)]-6-[[[3-(1H-imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

Q:[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-2-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

R:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-[2-(hydroxymethyl)-1H-imidazol-1-yl]propyl-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride 1.1 molar hydrate

S:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[3-[2-[[(dimethylamino)methylene]amino]-1H-imidazol-1-yl]propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 1.7 molar hydrochloride 2.6 molar hydrate

U:[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(1,4,5,6-tetrahydro-2-pyrimidinyl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride

as compared to an amdinocillin (mecillinam) were tested by the followingprocedure:

Drug dilutions are prepared in Mueller-Hinton broth ranging from 128 to0.008 μg/ml. The diluted agents are dispensed in 100 μl amounts into thewells of a 96-well tray and used immediately or frozen at -10° to -70°C. until needed. Using an automated inoculator, 1.5 μl of a 10⁻²dilution of an overnight culture is added to each well of the tray. Thetops of the trays are then sealed using transparent tape and incubatedovernight at 37° C. The trays are examined with the aid of a viewer. Thelowest concentration at which no growth is observed is considered to bethe minimum inhibitory concentration (MIC).

                                      TABLE 1                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   A     B     C     D     Amdinocillin                              __________________________________________________________________________    E. coli 257 0.125 0.25  2     0.125 0.125                                     E. coli 48  0.062 0.25  2     0.125 0.062                                     E. coli 4   0.062 8     8     0.125 0.062                                     E. coli 387-1                                                                             0.125 8     8     0.125 0.031                                     E. coli R-563                                                                             0.125 8     4     0.125 0.125                                     E. coli 503-455                                                                           2     1     128   1     2                                         E. coli 5152                                                                              16    16    >128  16    8                                         K. pneumoniae A                                                                           <0.008                                                                              0.062 4     0.031 0.031                                     K. pneumoniae HE7                                                                         >128  >128  >128  >128  >128                                      K. pneumoniae 503-964                                                                     0.016 0.25  8     0.25  0.125                                     K. pneumoniae 4964                                                                        2     0.5   >128  1     64                                        K. pneumoniae 5096                                                                        64    0.25  >128  >128  128                                       K. pneumoniae 35                                                                          0.25  1     8     0.25  0.125                                     K. pneumoniae 503-994                                                                     0.25  0.25  32    0.125 0.062                                     K. pneumoniae 8357                                                                        0.25  0.25  16    0.25  0.25                                      E. cloacae 6951                                                                           4     16    >128  16    16                                        E. cloacae 9570A                                                                          0.5   0.5   16    0.5   0.125                                     E. cloacae 5699                                                                           0.5   0.5   16    0.5   0.25                                      E. cloacae 9295                                                                           0.5   0.5   16    0.5   0.25                                      E. cloacae 24                                                                             0.5   2     32    0.5   0.125                                     E. cloacae P99                                                                            0.25  --    8     0.125 0.062                                     E. cloacae 214                                                                            0.125 1     16    0.25  0.125                                     E. aerogenes 8                                                                            32    0.25  >128  128   128                                       E. aerogenes 83                                                                           2     0.5   >128  16    8                                         E. aerogenes 503-478                                                                      0.062 2     128   8     4                                         C. freundii CDC6                                                                          0.125 0.25  16    0.25  0.125 0.062                               C. freundii 8ASM                                                                          0.062 0.062 4     0.062 0.062 0.031                               C. diversus CDC 1663-72                                                                   0.125 0.25  4     0.125 0.062 0.062                               S. typhi P58A                                                                             0.25  0.062 8     0.125 0.062 0.062                               S. schottmuelleri                                                                         0.125 0.25  4     0.125 0.062 0.031                               P. vulgaris 100                                                                           8     8     >128  16    0.5   0.5                                 P. vulgaris 101                                                                           16    1     128   32    64    0.25                                P. vulgaris ATCC 6380                                                                     0.125 0.5   4     0.125 0.031 0.062                               P. rettgeri ATCC 9250                                                                     0.5   0.5   16    0.5   0.125 0.062                               P. mirabilis  503-1136                                                                    8     8     128   16    2     0.5                                 P. mirabilis 620A                                                                         16    >128  >128  64    64    16                                  P. mirabilis 2                                                                            0.5   1     16    0.5   0.25  0.062                               P. mirabilis 90                                                                           1     2     32    1     0.25  0.25                                P. mirabilis 190                                                                          0.25  0.5   8     0.25  0.125 0.031                               S. marcescens 5805                                                                        1     1     32    2     1     1                                   S. marcescens SM                                                                          0.25  0.25  8     0.25  0.125 0.062                               S. marcescens S1                                                                          0.25  0.5   128   0.5   0.25  0.125                               S. marcescens S2                                                                          0.25  0.5   16    0.5   0.25  0.125                               S. marcescens S3                                                                          0.25  0.5   16    0.5   0.125 0.062                               S. marcescens S4                                                                          1     1     32    1     1     0.5                                 S. marcescens S5                                                                          2     2     64    2     1     1                                   S. marcescens S147                                                                        0.25  0.5   16    0.125 0.125 0.062                               S. marcescens S714                                                                        1     1     32    1     0.5   0.5                                 P. aeruginosa B                                                                           0.25  >128  8     0.25  0.125 >128                                P. aeruginosa Stone 130                                                                   >128  --    >128  >128  >128  --                                  P. aeruginosa POW 151                                                                     >128  >128  >128  >128  >128  > 128                               P. aeruginosa 8710                                                                        >128  >128  >128  >128  >128  >128                                P. aeruginosa 503-56                                                                      >128  --    >128  >128  >128  --                                  P. aeruginosa 503-820                                                                     >128  >128  >128  >1238 >128  128                                 P. aeruginosa 5700                                                                        0.25  >128  16    0.5   0.25  >128                                P. aeruginosa 5712                                                                        >128  >128  >128  >128  >128  >128                                P. aeruginosa 8780                                                                        >128  >128  >128  >128  >128  >128                                P. aeruginosa 6148B                                                                       >128  --    >128  >128  >128  --                                  S. faecalis C1                                                                            128   >128  >128  >128  >128  >128                                S. pyogenes 4                                                                             1     --    64    1     1     --                                  S. pyogenes 503-782                                                                       128   8     >128  >128  >128  1                                   S. pneumoniae SC                                                                          2     --    64    4     2     --                                  S. pneumoniae 6301                                                                        1     4     128   4     2     1                                   S. pneumoniae 6302                                                                        2     --    128   8     4     --                                  S. aureus Giorgio                                                                         8     32    >128  16    32    32                                  S. aureus 1059B                                                                           32    >128  >128  128   128   128                                 S. aureus Smith                                                                           8     --    >128  32    32    --                                  __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   C     F     G     E     Amdinocillin                              __________________________________________________________________________    E. coli 257 2     0.125 0.25  0.062 0.125 <0.008                              E. coli 48  2     0.062 0.062 0.062 0.062 0.016                               E. coli 4   8     0.062 0.25  4     0.062 2                                   E. coli 387-1                                                                             8     0.125 0.25  4     0.031 2                                   E. coli R-563                                                                             4     0.062 0.25  4     0.125 4                                   E. coli 503-455                                                                           128   2     4     2     2     1                                   E. coli 5152                                                                              >128  8     16    8     8     16                                  K. pneumoniae A                                                                           4     0.031 0.125 0.062 0.031 <0.008                              K. pneumoniae HE7                                                                         >128  >128  >128  >128  >128  >128                                K. pneumoniae 503-964                                                                     8     4     0.062 0.062 0.125 0.062                               K. pneumoniae 4964                                                                        >128  32    2     1     64    0.062                               K. pneumoniae 5096                                                                        >128  64    128   >128  128   >128                                K. pneumoniae 35                                                                          8     0.125 0.5   0.125 0.125 0.062                               K. pneumoniae 503-994                                                                     32    2     0.25  0.062 0.062 0.062                               K. pneumoniae 8357                                                                        16    1     1     0.062 0.25  0.062                               E. cloacae 6951                                                                           >128  8     16    8     16    8                                   E. cloacae 9570A                                                                          16    0.25  0.5   0.125 0.125 0.125                               E. cloacae 5699                                                                           16    0.25  0.5   0.125 0.25  0.062                               E. cloacae 9295                                                                           16    0.25  0.5   0.25  0.25  0.125                               E. cloacae 24                                                                             32    0.25  0.5   0.5   0.125 0.5                                 E. cloacae P99                                                                            8     0.125 0.5   0.125 0.062 0.062                               E. cloacae 214                                                                            16    0.125 0.25  0.5   0.125 0.5                                 E. aerogenes 8                                                                            >128  32    16    32    128   128                                 E. aerogenes 83                                                                           >128  16    0.5   0.5   8     4                                   E. aerogenes 503-478                                                                      128   4     8     1     4     1                                   C. freundii CDC6                                                                          16    0.062 0.25  0.125 0.125 0.062                               C. freundii 8 ASM                                                                         4     0.062 0.125 <0.008                                                                              0.062 <0.008                              C. diversus CDC 1663-72                                                                   4     0.062 0.125 0.062 0.062 0.062                               S. typhi P58A                                                                             8     0.062 0.25  0.062 0.062 0.016                               S. schottmuelleri                                                                         4     0.062 0.125 0.062 0.062 <0.008                              P. vulgaris 100                                                                           >128  16    32    8     0.5   0.5                                 P. vulgaris 101                                                                           128   16    16    4     64    0.5                                 P. vulgaris ATCC 6380                                                                     4     0.25  0.25  0.062 0.031 <0.008                              P. rettgeri ATCC 9250                                                                     16    0.25  1     0.5   0.125 <0.008                              P. mirabilis 503-1136                                                                     128   8     16    4     2     1                                   P. mirabilis 620A                                                                         >128  16    64    128   64    32                                  P. mirabilis 2                                                                            16    0.5   1     0.5   0.25  0.125                               P. mirabilis 90                                                                           32    0.5   1     0.5   0.25  0.5                                 P. mirabilis 190                                                                          8     0.25  0.5   0.25  0.125 0.062                               S. marcescens 5805                                                                        32    0.5   4     0.5   1     1                                   S. marcescens SM                                                                          8     0.125 1     0.125 0.125 0.062                               S. marcescens S1                                                                          128   0.5   1     1     0.25  0.062                               S. marcescens S2                                                                          16    0.25  1     0.5   0.25  0.125                               S. marcescens S3                                                                          16    0.25  1     0.25  0.125 0.125                               S. marcescens S4                                                                          32    2     2     0.5   1     0.5                                 S. marcescens S5                                                                          64    1     2     1     1     1                                   S. marcescens S147                                                                        16    0.25  1     0.5   0.125 0.125                               S. marcescens S714                                                                        32    1     8     1     0.5   2                                   P. aeruginosa B                                                                           8     0.25  0.25  >128  0.125 >128                                P. aeruginosa  Stone 130                                                                  >128  >128  >128  >128  >128  >128                                P. aeruginosa POW 151                                                                     >128  >128  >128  >128  >128  >128                                P. aeruginosa 8710                                                                        >128  >128  >128  >128  >128  >128                                P. aeruginosa 503-56                                                                      >128  >128  >128  >128  >128  >128                                P. aeruginosa 503-820                                                                     >128  >128  >128  >128  >128  >128                                P. aeruginosa 5700                                                                        16    0.5   1     >128  0.25  128                                 P. aeruginosa 5712                                                                        >128  >128  >128  >128  >128  >128                                P. aeruginosa 8780                                                                        >128  >12   >128  >128  >128  >128                                P. aeruginosa 6148B                                                                       >128  >128  >128  >128  >128  128                                 S. faecalis C1                                                                            >128  128   128   128   >128  >128                                S. pyogenes 4                                                                             64    0.5   1     0.5   1     1                                   S. pyogenes 503-782                                                                       >128  128   128   128   >128  >128                                S. pneumoniae SC                                                                          64    1     1     0.5   2     1                                   S. pneumoniae 6301                                                                        128   1     1     1     2     2                                   S. pneumoniae 6302                                                                        128   2     2     1     4     2                                   S. aureus Giorgio                                                                         >128  8     8     8     32    32                                  S. aureus 1059B                                                                           >128  64    128   64    128   128                                 S. aureus Smith                                                                           >128  8     8     8     32    16                                  __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   H     I     J     K     Amdinocillin                              __________________________________________________________________________    E. coli 257 0.25  0.031 0.125 0.5   0.125 0.062                               E. coli 48  0.062 0.031 8     0.25  0.062 4                                   E. coli 4   0.062 0.031 0.062 0.5   0.062 0.062                               E. coli 387-1                                                                             0.125 0.062 0.125 0.5   0.031 0.062                               E. coli R-563                                                                             0.062 0.062 0.125 0.5   0.125 0.062                               E. coli 503-455                                                                           1     1     1     4     2     0.25                                E. coli 5152                                                                              8     4     16    8     8     8                                   K. pneumoniae A                                                                           0.031 <0.008                                                                              0.062 0.25  0.031 0.062                               K. pneumoniae HE7                                                                         128   >128  >128  64    >128  64                                  K. pneumoniae 503-964                                                                     0.125 0.062 0.25  0.5   0.125 0.062                               K. pneumoniae 4964                                                                        64    0.25  0.5   0.5   64    0.062                               K. pneumoniae 5096                                                                        64    >128  128   16    128   32                                  k. pneumoniae 35                                                                          0.25  0.25  0.5   0.5   0.125 0.062                               K. pneumoniae 503-994                                                                     0.125 0.062 8     0.25  0.062 8                                   K. pneumoniae 8357                                                                        0.125 0.062 4     2     0.25  8                                   E. cloacae 6951                                                                           4     8     16    16    16    4                                   E. cloacae 9570A                                                                          0.25  0.125 0.5   1     0.125 0.062                               E. cloacae 5699                                                                           0.25  0.062 4     1     0.25  2                                   E. cloacae 9295                                                                           0.5   0.125 4     1     0.25  4                                   E. cloacae 24                                                                             0.25  0.125 0.5   1     0.125 0.062                               E. cloacae P99                                                                            0.062 0.031 8     0.5   0.062 8                                   E. cloacae 214                                                                            0.125 0.062 1     0.5   0.125 2                                   E. aerogenes 8                                                                            32    128   0.5   8     128   0.25                                E. aerogenes 83                                                                           16    1     1     8     8     4                                   E. aerogenes 503-478                                                                      8     1     8     4     4     8                                   C. freundii CDC6                                                                          0.062 0.031 64    0.5   0.125 32                                  C. freundii 8 ASM                                                                         0.031 0.031 0.125 0.25  0.062 0.006                               C. diversus CDC 1663-72                                                                   0.062 0.031 0.031 0.25  0.062 0.062                               S. typhi P58A                                                                             0.062 0.062 8     0.5   0.062 8                                   S. schottmuelleri                                                                         0.062 0.031 0.062 0.5   0.062 0.062                               P. vulgaris 100                                                                           4     4     8     16    0.5   0.5                                 P. vulgaris 101                                                                           8     128   8     16    64    8                                   P. vulgaris ATCC 6380                                                                     0.062 0.062 0.125 0.5   0.031 0.016                                P. rettgeri ATCC 9250                                                                    0.25  0.25  16    2     0.125 8                                   P. mirabilis 503-1136                                                                     4     4     8     8     2     8                                   P. mirabilis 620A                                                                         16    32    >128  16    64    8                                   P. mirabilis 2                                                                            0.25  0.25  8     4     0.25  8                                   P. mirabilis 90                                                                           0.125 4     1     8     0.25  0.25                                P. mirabilis 190                                                                          0.125 0.125 0.5   0.5   0.125 0.062                               S. marcescens 5805                                                                        0.5   0.25  1     8     1     0.5                                 S. marcescens SM                                                                          0.125 0.062 0.5   2     0.125 0.062                               S. marcescens S1                                                                          0.125 0.062 0.5   2     0.25  0.125                               S. marcescens S2                                                                          0.062 0.062 0.25  2     0.25  0.125                               S. marcescens S3                                                                          0.125 0.062 0.25  4     0.125 0.062                               S. marcescens S4                                                                          0.5   0.25  1     8     1     0.5                                 S. marcescens S5                                                                          0.5   0.25  0.5   8     1     0.5                                 S. marcescens S147                                                                        0.031 0.062 0.25  2     0.125 0.062                               S. marcescens S714                                                                        0.25  0.125 0.5   8     0.5   0.5                                 P. aeruginosa B                                                                           0.5   0.062 0.25  0.25  0.125 0.062                               P. aeruginosa Stone 130                                                                   >128  >128  >128  >128  >128  128                                 P. aeruginosa POW 151                                                                     >128  >128  >128  >128  >128  >128                                P. aeruginosa 8710                                                                        128   128   >128  >128  >128  128                                 P. aeruginosa 503-56                                                                      32    128   64    >128  >128  128                                 P. aeruginosa 503-820                                                                     64    128   >128  >128  >128  64                                  P. aeruginosa 5700                                                                        0.125 0.062 0.5   4     0.25  0.062                               P. aeruginosa 5712                                                                        128   >128  >128  >128  >128  >128                                P. aeruginosa 8780                                                                        >128  >128  >128  >128  >128  >128                                P. aeruginosa 6148B                                                                       64    128   128   >128  >128  64                                  S. faecalis C1                                                                            64    >128  128   128   >128  128                                 S. pyogenes 4                                                                             1     1     4     0.5   1     2                                   S. pyogenes 503-782                                                                       64    >128  128   128   >128  128                                 S. pneumoniae SC                                                                          1     4     4     1     2     2                                   S. pneumoniae 6301                                                                        1     2     1     1     2     2                                   S. pneumoniae 6302                                                                        1     4     4     1     4     2                                   S. aureus Giorgio                                                                         8     16    8     8     32    8                                   S. aureus 1059B                                                                           128   64    >128  128   128   64                                  S. aureus Smith                                                                           8     16    8     8     32    8                                   __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   L      M     N      Amdinocillin                                  __________________________________________________________________________    E. coli 257 1      0.125 0.031  0.125                                         E. coli 48  0.5    0.125 0.031  0.062                                         E. coli 4   0.125  0.062 0.016  0.062                                         E. coli 378-1                                                                             0.25   0.062 0.016  0.031                                         E. coli R-563                                                                             0.25   0.062 0.031  0.125                                         E. coli 503-455                                                                           4      2     1      2                                             E. coli 5152                                                                              32     16    8      8                                             K. pneumoniae A                                                                           0.25   0.062 0.016  0.031                                         K. pneumoniae HE7                                                                         >128   >128  >128   >128                                          K. pneumoniae 503-964                                                                     2      0.25  0.062  0.125                                         K. pneumoniae 4964                                                                        64     2     32     64                                            K. pneumoniae 5096                                                                        64     >128  >128   128                                           K. pneumoniae 35                                                                          2      1     0.125  0.125                                         K. pneumoniae 503-994                                                                     1      0.25  0.062  0.062                                         K. pneumoniae 8357                                                                        2      1     0.125  0.25                                          E. cloacae 6951                                                                           8      32    8      16                                            E. cloacae 9570A                                                                          2      0.25  0.062  0.125                                         E. cloacae 5699                                                                           1      0.25  0.062  0.25                                          E. cloacae 9295                                                                           2      0.5   0.125  0.25                                          E. cloacae 24                                                                             1      0.5   0.125  0.125                                         E. cloacae P99                                                                            0.25   0.062 0.016  0.062                                         E. cloacae 214                                                                            1      0.25  0.062  0.125                                         E. aerogenes 8                                                                            32     32    32     128                                           E. aerogenes 83                                                                           2      2     8      8                                             E. aerogenes 503-478                                                                      8      4     4      4                                             C. freundii CDC6                                                                          0.5    0.125 0.031  0.125                                         C. freundii 8 ASM                                                                         0.25   0.062 0.031  0.062                                         C. diversus CDC 1663-72                                                                   0.5    0.062 0.031  0.062                                         S. typhi P58A                                                                             0.5    0.062 0.031  0.062                                         S. schottmuelleri                                                                         0.25   0.062 0.031  0.062                                         P. vulgaris 100                                                                           32     8     0.5    0.5                                           P. vulgaris 101                                                                           32     16    64     64                                            P. vulgaris ATCC 6380                                                                     0.25   0.25  0.031  0.031                                         P. rettgeri ATCC 9250                                                                     1      0.5   0.125  0.125                                         P. mirabilis 503-1136                                                                     8      8     4      2                                             P. mirabilis 620A                                                                         >128   >128  128    64                                            P. mirabilis 2                                                                            1      0.5   0.125  0.25                                          P. mirabilis 90                                                                           2      0.5   0.125  0.25                                          P. mirabilis 190                                                                          0.5    0.5   0.125  0.125                                         S. marcescens 5805                                                                        8      1     0.25   1                                             S. marcescens  SM                                                                         1      0.125 0.062  0.125                                         S. marcescens S1                                                                          0.5    0.25  2      0.25                                          S. marcescens S2                                                                          0.5    0.25  0.062  0.25                                          S. marcescens S3                                                                          0.5    0.125 0.062  0.125                                         S. marcescens S4                                                                          2      1     0.25   1                                             S. marcescens S5                                                                          4      1     0.25   1                                             S. marcescens S147                                                                        1      0.25  0.062  0.125                                         S. marcescens S714                                                                        2      0.5   0.125  0.5                                           P. aeruginosa B                                                                           0.5    0.25  0.062  0.125                                         P. aeruginosa Stone 130                                                                   >128   >128  >128   >128                                          P. aeruginosa POW 151                                                                     >128   >128  >128   >128                                          P. aeruginosa 8710                                                                        128    64    32     >128                                          P. aeruginosa 503-56                                                                      64     32    16     >128                                          P. aeruginosa 503-820                                                                     128    64    16     >128                                          P. aeruginosa 5700                                                                        2      0.125 0.062  0.25                                          P. aeruginosa 5712                                                                        >128   128   64     >128                                          P. aeruginosa 8780                                                                        >128   128   128    >128                                          P. aeruginosa 6148B                                                                       128    32    32     >128                                          S. faecalis C1                                                                            32     32    64     >128                                          S. pyogenes 4                                                                             0.5    1     1      1                                             S. pyogenes 503-782                                                                       32     32    64     >128                                          S. pneumoniae SC                                                                          1      1     1      2                                             S. pneumoniae 6301                                                                        0.5    1     1      2                                             S. pneumoniae 6302                                                                        1      1     2      4                                             S. aureus Giorgio                                                                         2      2     8      32                                            S. aureus 1059B                                                                           64     32    64     128                                           S. aureus Smith                                                                           4      4     8      32                                            __________________________________________________________________________

                  TABLE 5                                                         ______________________________________                                                    In Vitro                                                                      MIC: μg/ml                                                     Organisms     O         P         Amdinocillin                                ______________________________________                                        E. coli 257   0.125     2         0.125                                       E. coli 48    0.125     2         0.062                                       E. coli 4     0.125     2         0.062                                       E. coli 387-1 0.125     4         0.031                                       E. coli R-563 0.125     2         0.125                                       E. coli 503-455                                                                             1         64        2                                           E. coli 5152  16        >128      8                                           K. pneumoniae A                                                                             0.062     2         0.031                                       K. pneumoniae HE7                                                                           >128      128       >128                                        K. pneumoniae 503-964                                                                       0.5       8         0.125                                       K. pneumoniae 4964                                                                          64        64        64                                          K. pneumoniae 5096                                                                          64        64        128                                         K. pneumoniae 35                                                                            1         16        0.125                                       K. pneumoniae 503-994                                                                       0.5       8         0.062                                       K. pneumoniae 8357                                                                          0.5       8         0.25                                        E. cloacae 6951                                                                             16        >128      16                                          E. cloacae 9570A                                                                            0.5       8         0.125                                       E. cloacae 5699                                                                             0.5       8         0.25                                        E. cloacae 9295                                                                             1         8         0.25                                        E. cloacae 24 1         8 0.125                                               E. cloacae P99                                                                              0.062     8         0.062                                       E. cloacae 214                                                                              0.5       8         0.125                                       E. aerogenes 8                                                                              32        16        128                                         E. aerogenes 83                                                                             8         8         8                                           E. aerogenes 503-478                                                                        >128      >128      4                                           C. freundii CDC6                                                                            0.125     4         0.125                                       C. freundii 8 ASM                                                                           0.062     2         0.062                                       C. diversus CDC 1663-72                                                                     0.125     2         0.062                                       S. typhi P58A 0.125     2         0.062                                       S. schottmuelleri                                                                           0.125     2         0.062                                       P. vulgaris 100                                                                             8         128       0.5                                         P. vulgaris 101                                                                             32        64        64                                          P. vulgaris ATCC 6380                                                                       0.25      0.5       0.031                                       P. rettgeri ATCC 9250                                                                       0.5       4         0.125                                       P. mirabilis 5036-1136                                                                      4         64        2                                           P. mirabilis 620A                                                                           4         >128      64                                          P. mirabilis 2                                                                              1         8         0.25                                        P. mirabilis 90                                                                             0.5       8         0.25                                        P. mirabilis 190                                                                            0.5       4         0.125                                       S. marcescens 5805                                                                          8         128       1                                           S. marcescens SM                                                                            0.5       8         0.125                                       S. marcescens S1                                                                            0.5       8         0.25                                        S. marcescens S2                                                                            0.5       8         0.25                                        S. marcescens S3                                                                            0.25      8         0.125                                       S. marcescens S4                                                                            2         >128      1                                           S. marcescens S5                                                                            4         > 128     1                                           S. marcescens S147                                                                          0.25      8         0.125                                       S. marcescens S714                                                                          1         32        0.5                                         P. aeruginosa B                                                                             0.5       8         0.125                                       P. aeruginosa Stone 130                                                                     >128      >128      >128                                        P. aeruginosa POW 151                                                                       >128      >128      >128                                        P. aeruginosa 8710                                                                          >128      >128      >128                                        P. aeruginosa 503-56                                                                        >128      >128      >128                                        P. aeruginosa 503-820                                                                       >128      >128      >128                                        P. aeruginosa 5700                                                                          0.5       8         0.25                                        P. aeruginosa 5712                                                                          >128      >128      >128                                        P. aeruginosa 8780                                                                          >128      >128      >128                                        P. aeruginosa 6148B                                                                         >128      >128      >128                                        S. faecalis C1                                                                              32        64        >128                                        S. pyogenes 4 0.5       0.5       1                                           S. pyogenes 503-782                                                                         32        64        >128                                        S. pneumoniae SC                                                                            1         1         2                                           S. pneumoniae 6301                                                                          1         1         2                                           S. pneumoniae 6302                                                                          1         1         4                                           S. aureus Giorgio                                                                           4         4         32                                          S. aureus 1059B                                                                             >128      64        128                                         S. aureus Smith                                                                             4         2         32                                          ______________________________________                                    

                                      TABLE 6                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   O     L     Q     M     Amdinocillin                              __________________________________________________________________________    E. coli 257 0.125 1     0.062*                                                                              0.125 0.125 0.062                               E. coli 48  0.125 0.5   8     0.125 0.062 4                                   E. coli 4   0.125 0.125 0.062 0.062 0.062                                     E. coli 387-1                                                                             0.125 0.25  0.062 0.062 0.031 0.062                               E. coli R-563                                                                             0.125 0.25  0.062 0.062 0.125 0.062                               E. coli 503-455                                                                           1     4     1     2     2     0.25                                E. coli 5152                                                                              16    32    64    16    8     8                                   K. pneumoniae A                                                                           0.062 0.25  0.062 0.062 0.031 0.062                               K. pneumoniae HE7                                                                         >128  >128  >128  >128  >128  64                                  K. pneumoniae 503-964                                                                     0.5   2     0.5   0.25  0.125 0.062                               K. pneumoniae 4964                                                                        64    64    4     2     64    0.062                               K. pneumoniae 5096                                                                        64    64    128   >128  128   32                                  K. pneumoniae 35                                                                          1     2     0.25  1     0.125 0.062                               K. pneumoniae 503-994                                                                     0.5   1     8     0.25  0.062 8                                   K. pneumoniae 8357                                                                        0.5   2     4     1     0.25  8                                   E. cloacae 6951                                                                           16    8     16    32    16    4                                   E. cloacae 9570A                                                                          0.5   2     0.125 0.25  0.125 0.062                               E. cloacae 5699                                                                           0.5   1     4     0.25  0.25  2                                   E. cloacae 9295                                                                           1     2     4     0.5   0.25  4                                   E. cloacae 24                                                                             1     1     0.5   0.5   0.125 0.062                               E. cloacae P99                                                                            0.062 0.25  8     0.062 0.62  8                                   E. cloacae 214                                                                            0.5   1     0.5   0.25  0.125 2                                   E. aerogenes 8                                                                            32    32    0.125 32    128   0.25                                E. aerogenes 83                                                                           8     2     4     2     8     4                                   E. aerogenes 503-478                                                                      >128  8     16    4     4     8                                   C. freundii CDC6                                                                          0.125 0.5   64    0.125 0.125 32                                  C. freundii 8 ASM                                                                         0.062 0.25  0.062 0.062 0.062 0.006                               C. diversus CDC 1663-72                                                                   0.125 0.5   0.062 0.062 0.062 0.062                               S. typhi P58A                                                                             0.125 0.5   8     0.062 0.062 8                                   S. schottmuelleri                                                                         0.125 0.25  0.062 0.062 0.062 0.062                               P. vulgaris 100                                                                           8     32    1     8     0.5   0.5                                 P. vulgaris 101                                                                           32    32    8     16    64    8                                   P. vulgaris ATCC 6380                                                                     0.25  0.25  0.016 0.25  0.031 0.016                               P. rettgeri ATCC 9250                                                                     0.5   1     16    0.5   0.125 8                                   P. mirabilis 503-1136                                                                     4     8     8     8     2     8                                   P. mirabilis 620A                                                                         4     >128  >128  >128 64                                                                             8                                         P. mirabilis 2                                                                            1     1     8     0.5   0.25  8                                   P. mirabilis 90                                                                           0.5   2     0.5   0.5   0.25  0.25                                P. mirabilis 190                                                                          0.5   0.5   0.25  0.5   0.125 0.062                               S. marcescens 5805                                                                        8     8     1     1     1     0.5                                 S. marcescens SM                                                                          0.5   1     0.125 0.125 0.125 0.062                               S. marcescens S1                                                                          0.5   0.5   0.125 0.25  0.25  0.125                               S. marcescens S2                                                                          0.5   0.5   0.125 0.25  0.25  0.125                               S. marcescens S3                                                                          0.25  0.5   0.125 0.125 0.125 0.062                               S. marcescens S4                                                                          2     2     0.5   1     1     0.5                                 S. marcescens S5                                                                          4     4     0.5   1     1     0.5                                 S. marcescens S147                                                                        0.25  1     0.125 0.25  0.125 0.062                               S. marcescens S714                                                                        1     2     0.25  0.5   0.5   0.5                                 P. aeruginosa B                                                                           0.5   0.5   0.25  0.25  0.125 0.062                               P. aeruginosa Stone 130                                                                   >128  >128  >128  >128  >128  128                                 P. aeruginosa POW 151                                                                     >128  >128  >128  >128  >128  >128                                P. aeruginosa 8710                                                                        >128  128   128   64    >128  128                                 P. aeruginosa 503-56                                                                      128   64    64    32    >128  128                                 P. aeruginosa 503-820                                                                     >128  128   128   64    >128  64                                  P. aeruginosa 5700                                                                        0.5   2     0.125 0.125 0.25  0.062                               P. aeruginosa 5712                                                                        >128  >128  >128  128   >128  >128                                P. aeruginosa 8780                                                                        >128  >128  >128  128   >128  >128                                P. aeruginosa 6148B                                                                       >128  128   128   32    >128  64                                  S. faecalis C1                                                                            32    32    128   32    >128  128                                 S. pyogenes 4                                                                             0.5   0.5   1     1     1     2                                   S. pyogenes 503-782                                                                       32    32    128   32    >128  128                                 S. pneumoniae SC                                                                          1     1     2     1     2     2                                   S. pneumoniae 6301                                                                        1     0.5   1     1     2     2                                   S. pneumoniae 6302                                                                        1     1     2     1     4     2                                   S. aureus Giorgio                                                                         4     2     8     2     32    8                                   S. aureus 1059B                                                                           >128  64    128   32    128   64                                  S. aureus Smith                                                                           4     4     8     4     32    8                                   __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   R      S     E      Amdinocillin                                  __________________________________________________________________________    E. coli 257 0.016  0.25  0.062  <0.008                                        E. coli 48  0.016  0.5   0.062  0.016                                         E. coli 4   2      4     4      2                                             E. coli 387-1                                                                             2      2     4      2                                             E. coli R-563                                                                             4      8     4      4                                             E. coli 503-455                                                                           0.5    1     2      1                                             E. coli 5152                                                                              4      8     8      16                                            K. pneumoniae A                                                                           <0.008 0.5   0.062  <0.008                                        K. pneumoniae HE7                                                                         >128   >128  >128   >128                                          K. pneumoniae 503-964                                                                     0.016  0.5   0.062  0.062                                         K. pneumoniae 4964                                                                        0.5    0.5   1      0.062                                         K. pneumoniae 5096                                                                        8      >128  >128   >128                                          K. pneumoniae 35                                                                          0.062  0.5   0.125  0.062                                         K. pneumoniae 503-994                                                                     0.016  0.5   0.062  0.062                                         K. pneumoniae 8357                                                                        0.062  0.5   0.062  0.062                                         E. cloacae 6951                                                                           8      8     8      8                                             E. cloacae 9570A                                                                          0.062  1     0.125  0.125                                         E. cloacae 5699                                                                           0.062  1     0.125  0.062                                         E. cloacae 9295                                                                           0.125  1     0.25   0.125                                         E. cloacae 24                                                                             0.25   1     0.5    0.5                                           E. cloacae P99                                                                            0.062  1     0.125  0.062                                         E. cloacae 214                                                                            0.5    4     0.5    0.5                                           E. aerogenes 8                                                                            32     32    32     128                                           E. aerogenes 83                                                                           1      4     0.5    4                                             E. aerogenes 503-478                                                                      0.5    2     1      1                                             C. freundii CDC6                                                                          0.062  0.5   0.125  0.062                                         C. freundii 8ASM                                                                          <0.008 0.125 <0.008 <0.008                                        C. diversus CDC 1663-72                                                                   0.016  0.5   0.062  0.062                                         S. typhi P58A                                                                             0.062  0.25  0.062  0.016                                         S. schottmuelleri                                                                         <0.008 0.25  0.062  <0.008                                        P. vulgaris 100                                                                           2      8     8      0.5                                           P. vulgaris 101                                                                           1      8     4      0.5                                           P. vulgaris ATCC 6380                                                                     <0.008 1     0.062  <0.008                                        P. rettgeri ATCC 9250                                                                     0.062  0.25  0.5    <0.008                                        P. mirabilis 503-1136                                                                     4      8     4      1                                             P. mirabilis 620A                                                                         64     >128  128    32                                            P. mirabilis 2                                                                            0.25   2     0.5    0.125                                         P. mirabilis 90                                                                           0.5    4     0.5    0.5                                           P. mirabilis 190                                                                          0.062  1     0.25   0.62                                          S. marcescens 5805                                                                        1      4     0.5    1                                             S. marcescens SM                                                                          0.062  2     0.125  0.062                                         S. marcescens S1                                                                          0.062  4     1      0.062                                         S. marcescens S2                                                                          0.125  2     0.5    0.125                                         S. marcescens S3                                                                          0.125  2     0.25   0.125                                         S. marcescens S4                                                                          0.5    4     0.5    0.5                                           S. marcescens S5                                                                          1      4     1      1                                             S. marcescens S147                                                                        0.125  2     0.5    0.125                                         S. marcescens S714                                                                        1      4     1      2                                             P. aeruginosa B                                                                           128    >128  >128   >128                                          P. aeruginosa Stone 130                                                                   >128   >128  >128   >128                                          P. aeruginosa POW 151                                                                     >128   >128  >128   >128                                          P. aeruginosa 8710                                                                        >128   >128  >128   >128                                          P. aeruginosa 503-56                                                                      >128   >128  >128   >128                                          P. aeruginosa 503-820                                                                     128    >128  >128   >128                                          P. aeruginosa 5700                                                                        >128   >128  >128   128                                           P. aeruginosa 5712                                                                        >128   >128  >128   >128                                          P. aeruginosa 8780                                                                        >128   >128  >128   >128                                          P. aeruginosa 6148B                                                                       128    >128  >128   128                                           S. faecalis C1                                                                            128    128   128    >128                                          S. pyogenes 4                                                                             0.5    0.25  0.5    1                                             S. pyogenes 503-782                                                                       128    128   128    >128                                          S. pneumoniae SC                                                                          0.5    0.5   0.5    1                                             S. pneumoniae 6301                                                                        1      2     1      2                                             S. pneumoniae 6302                                                                        1      1     1      2                                             S. aureus Giorgio                                                                         8      8     8      32                                            S. aureus 1059B                                                                           64     64    64     128                                           S. aureus Smith                                                                           8      8     8      16                                            __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________                In Vitro                                                                      MIC: μg/ml                                                     Organisms   J      Q     T      Amdinocillin                                  __________________________________________________________________________    E. coli 257 0.125  0.062 0.25   0.062                                         E. coli 48  8      8     8      4                                             E. coli 4   0.062  0.062 0.125  0.062                                         E. coli 387-1                                                                             0.125  0.062 0.125  0.062                                         E. coli R-563                                                                             0.125  0.062 0.062  0.062                                         E. coli 503-455                                                                           1      1     4      0.25                                          E. coli 5152                                                                              16     64    32     8                                             K. pneumoniae A                                                                           0.062  0.062 0.062  0.062                                         K. pneumoniae HE7                                                                         >128   >128  >128   64                                            K. pneumoniae 503-964                                                                     0.25   0.5   0.25   0.062                                         K. pneumoniae 4964                                                                        0.5    4     0.5    0.062                                         K. pneumoniae 5096                                                                        128    128   128    32                                            K. pneumoniae 35                                                                          0.5    0.25  0.5    0.062                                         K. pneumoniae 503-994                                                                     8      8     8      8                                             K. pneumoniae 8357                                                                        4      4     16     8                                             E. cloacae 6951                                                                           16     16    16     4                                             E. cloacae 9570A                                                                          0.5    0.125 0.5    0.062                                         E. cloacae 5699                                                                           4      4     4      2                                             E. cloacae 9295                                                                           4      4     8      4                                             E. cloacae 24                                                                             0.5    0.5   0.5    0.062                                         E. cloacae P99                                                                            8      8     8      8                                             E. cloacae 214                                                                            1      0.5   0.5    2                                             E. aerogenes 8                                                                            0.5    0.125 0.5    0.25                                          E. aerogenes 83                                                                           1      4     4      4                                             E. aerogenes 503-478                                                                      8      16    16     8                                             C. freundii CDC6                                                                          64     64    64     32                                            C. freundii 8ASM                                                                          0.125  0.062 0.062  0.016                                         C. diversus CDC 1663-72                                                                   0.031  0.062 0.062  0.062                                         S. typhi P58A                                                                             8      8     8      8                                             S. schottmuelleri                                                                         0.062  0062  0.062  0.062                                         P. vulgaris 100                                                                           8      1     8      0.5                                           P. vulgaris 101                                                                           8      8     8      8                                             P. vulgaris ATCC 6380                                                                     0.125  0.016 0.062  0.016                                         P. rettgeri ATCC 9250                                                                     16     16    64     8                                             P. mirabilis 503-1136                                                                     8      8     8      8                                             P. mirabilis 620A                                                                         >128   >128  128    8                                             P. mirabilis 2                                                                            8      8     8      8                                             P. mirabilis 90                                                                           1      0.5   1      0.25                                          P. mirabilis 190                                                                          0.5    0.25  0.5    0.062                                         S. marcescens 5805                                                                        1      1     4      0.5                                           S. marcescens MS                                                                          0.5    0.125 0.5    0.062                                         S. marcescens S1                                                                          0.5    0.125 0.5    0.125                                         S. marcescens S2                                                                          0.25   0.125 0.5    0.125                                         S. marcescens S3                                                                          0.25   0.125 0.5    0.062                                         S. marcescens S4                                                                          1      0.5   2      0.5                                           S. marcescens S5                                                                          0.5    0.5   1      0.5                                           S. marcescens S147                                                                        0.25   0.125 0.5    0.062                                         S. marcescens S714                                                                        0.5    0.25  0.5    0.5                                           P. aeruginosa B                                                                           0.25   0.25  0.5    0.062                                         P. aeruginosa Stone 130                                                                   >128   >128  >128   128                                           P. aeruginosa POW 151                                                                     >128   >128  >128   >128                                          P. aeruginosa 8710                                                                        >128   128   >128   128                                           P. aeruginosa 503-56                                                                      64     64    64     128                                           P. aeruginosa 503-820                                                                     >128   128   >128   64                                            P. aeruginosa 5700                                                                        0.5    0.125 0.5    0.062                                         P. aeruginosa 5712                                                                        >128   >128  >128   >128                                          P. aeruginosa 8780                                                                        >128   >128  >128   >128                                          P. aeruginosa 6148B                                                                       128    128   128    64                                            S. faecalis C1                                                                            128    128   128    128                                           S. pyogenes 4                                                                             4      1     4      2                                             S. pyogenes 503-782                                                                       128    128   >128   128                                           S. pneumoniae SC                                                                          4      2     4      2                                             S. pneumoniae 6301                                                                        1      1     2      2                                             S. pneumoniae 6302                                                                        4      2     4      2                                             S. aureus Giorgio                                                                         8      8     8      8                                             S. aureus 1059B                                                                           >128   128   >128   64                                            S. aureus Smith                                                                           8      8     8      8                                             __________________________________________________________________________

EXAMPLE 70

In Tables 9-14, the results of the in vivo activity against certainmicroorganisms of compounds I, M and N as given. The results are for thein vivo activities of these compounds alone or in combination with otherantibiotic compounds such as amdinocillin, ceftriaxone, ampicillin,carbenicillin and cephalothin. The results in these Tables and the PD₅₀'s were determined by the procedure set forth on page 160 in Beskid etal., Antimicrobial Agents and Chemotherapy, Vol. 20, No. 2 pp. 159-167(Aug. 1981) for "in vivo studies".

In the Tables, the fractional inhibitory concentration index (FIC) forsynergistic combination of a compound of this invention (X) with knownantibiotic compound (Y) is determined by the following formula:

    FIC=(PD.sub.50 (X combination)/PD.sub.50 (X alone)+(PD.sub.50 (Y combination)/PD.sub.50 (Y alone)

An FIC of ≦0.60 is indicative of synergy. The synergy rating in theTables is as follows:

    0.50 to 0.60=+

    0.40 to 0.49=++

    0.3 to 0.39=+++

    <0.3=++++

In the combination, the parts are parts by weight, i.e. 10 to 1 is 10parts by weight to 1 part by weight.

EXAMPLE 71

A 100 mg injectable composition was prepared by aseptically filling inpower form 100 mg. of[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-1-yl-methyl)-1-piperidinyl]methylene]amino-3,3-dimethyl-6-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid into a 1 ml sterile vial. To the vial there was added sufficientsterile distilled water to fill the vial. In this manner, thiscomposition was ready for injection.

EXAMPLE 72

A 200 mg injectable composition was prepared by aseptically filling inpowder form 200 mg of[2S-(2alpha,5alpha,6beta)]-6-[[[4-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride into a 1 ml sterile vial. To the vial there was addedsufficient sterile distilled water to fill the vial. In this manner,this composition was ready for injection.

EXAMPLE 73

A 500 mg injectable composition was prepared by aseptically filling inpowder form 500 mg of[2S-(2alpha,5alpha,6beta)]-6-[[[4-(1H-imidazol-2-yl-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid hydrochloride trihydrate in a 1 ml sterile vial. To the vial therewas added sufficient sterile distilled water to fill the vial. In thismanner, this composition was ready for injection.

                  TABLE 9                                                         ______________________________________                                                       PD.sub.50 : mg/kg sc                                           Infecting Organism                                                                             I         Amdinocillin                                       ______________________________________                                        E. coli 257      <0.2      <0.025                                             5152             >250      >250                                               4                1.9       4.6                                                E. aerogenes 8   >250      >250                                               83               >250      >250                                               S. marcescens SM >250      >250                                               S5               >250      >250                                               P. aeruginosa 503-56                                                                           >250      >250                                               POW151           111       143                                                S. aureus Smith  61        69                                                 Giorgio          >250      >250                                               S. pyogenes 4    11        60                                                 503-782          59        80                                                 S. pneumoniae SC 3.6       <2                                                 6302             202       204                                                6301             >250      192                                                S. faecalis C1   >250      >250                                               ______________________________________                                    

                                      TABLE 10                                    __________________________________________________________________________    In Vivo Antibacterial Activity                                                          Challenge                                                                           Number of                                                                           PD.sub.50 : mg/kg sc                                    Infecting Organism                                                                      LD.sub.50 s                                                                         Treatments                                                                          M     Amdinocillin                                                                         Ceftriaxone                                __________________________________________________________________________    S. aureus Smith                                                                         48    2     <5    22     --                                                   100   2     6.7   12     --                                         S. pyogenes 4                                                                           100   2     <2    8.1    >2                                         P. aeruginosa 6148B                                                                     4.5   3     <20   --     <5                                                   33    3     <20   --     8                                          P. aeruginosa 6720                                                                      3511  2     29    >250   14                                         P. aeruginosa 6719                                                                      2249  3     34    --     18                                         P. aeruginosa 8710                                                                      10    2     54    >250   --                                                   562   2     59    >250   --                                         P. aeruginosa 503-56                                                                    4.7   2     67    >250   --                                                   100   2     100   >250   --                                         P. aeruginosa 6799                                                                      48    2     >250  117    <10                                        E. coli 257                                                                             >10.sup.4                                                                           1     1.5   <1     <1                                         E. coli 5152                                                                            2717  2     134   84     <5                                          K. pneumoniae HE7                                                                      750   2     71    >250   <1                                         E. cloacae 6951                                                                         562   2     15    18     <1                                         E. aerogenes 8                                                                          24    2     60    >250   6.8                                        __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________    In Vivo Antibacterial Activities                                                        Challenge                                                                           Number of                                                                           PD.sub.50 : mg/kg sc                                    Infecting Organism                                                                      LD.sub.50 s                                                                         Treatments                                                                          N     Amdinocillin                                                                         Ceftriaxone                                __________________________________________________________________________    S. aureus Smith                                                                         70    2     12    13     3.2                                        S. pyogenes 4                                                                           3.3   2     4.3   11     <2                                         P. aeruginosa 6148B                                                                     32    2     37    >250   62                                         P. aeruginosa 6720                                                                      35    2     20    >250   15                                         P. aeruginosa 6719                                                                      2290  2     22    <20    15                                         P. aeruginosa 8710                                                                      >10.sup.4                                                                           2     50    >250   31                                         P. aeruginosa 503-56                                                                    50    2     43    >250   >250                                       P. aeruginosa 6799                                                                      71    2     >250  >250   16                                         E. coli 257                                                                             >10.sup.4                                                                           1     <1    <2     <1                                         E. coli 5152                                                                            4780  2     30    150    <2                                         K. pneumoniae HE7                                                                       1000  2     >250  >250   0.39                                       E. cloacae 6951                                                                         3162  2     <2    2.5    0.03                                       E. aerogenes 8                                                                          10    2     >250  167    6.9                                        S. marcescens S3                                                                        32    2     <0.5  2.7    0.03                                       S. marcescens SM                                                                        489   2     19    >250   <2                                         S. pneumoniae 6302                                                                      1000  1     78    >250   0.22                                       S. faecalis C1                                                                          10    1     62    >250   50                                         E. coli 387-1                                                                           127   1     <0.2  <0.2   0.09                                       K. pneumoniae 8357                                                                      >10.sup.4                                                                           1     6.2   6.7    0.03                                       E. cloacae 214                                                                          3.8   2     <10   <10    <10                                        C. freundii 8ASM                                                                        1000  1     0.22  0.76   0.15                                       S. schottmuelleri                                                                       163   1     <0.05 0.25   <0.5                                       P. vulgaris 100                                                                         100   1     67    45     0.05                                       P. mirabilis 190                                                                        10.sup.4                                                                            1     140   117    0.007                                      __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________    In Vivo Activities                                                                        PD.sub.50 : mg/kg sc                                              __________________________________________________________________________                            10 + 1                                                                        Ampicillin                                                                    +      FIC Synergy rating                             Infecting Organism                                                                        Ampicillin                                                                           M    M      10 + 1                                                                            10 + 1                                     __________________________________________________________________________    K. pneumoniae 503-990A                                                                    29     9.4  1.4 + 0.14                                                                           0.063                                                                             ++++                                       K. pneumoniae 39                                                                          9.4    5     1 + 0.1                                                                             0.126                                                                             ++++                                       __________________________________________________________________________                            10 + 1                                                                        Cephalothin                                                                   +                                                                 Cephalothin                                                                          M    M                                                     __________________________________________________________________________    E. coli BC5524                                                                            <250   80   41 + 4.1                                                                             0.215                                                                             ++++                                       K. pneumoniae R2296                                                                       69     >250 34 + 3.4                                                                             0.507                                                                             +                                          E. cloacae 4633                                                                           >250   34   80 + 8 0.555                                                                             +                                          __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________    In Vivo Activities                                                                        PD.sub.50 : mg/kg sc                                              __________________________________________________________________________                             10 + 1                                                                        Ampicillin                                                                    +      FIC Synergy rating                            Infecting Organism                                                                        Ampicillin                                                                           N     N      10 + 1                                                                            10 + 1                                    __________________________________________________________________________    K. pneumoniae 503-990A                                                                    16     5.5   1.6 + 0.16                                                                           0.129                                                                             ++++                                      K. pneumoniae 39                                                                          18     18    1.2 + 0.12                                                                           0.074                                                                             ++++                                                               10 + 1                                                                        Cephalothin                                                                   +                                                                Cephalothin                                                                          N     N                                                    __________________________________________________________________________    E. coli BC5524                                                                            >250    114  >250 + >25                                                                           >1  NS                                        K. pneumoniae R2296                                                                       31     >250   5.5 + 0.55                                                                          0.179                                                                             ++++                                      E. cloacae 4633                                                                           >250     12    53 + 5.3                                                                           0.654                                                                             NS                                        __________________________________________________________________________                Challenge           1 + 1                                                     LD.sub.50 s                                                                          Ceftriaxone                                                                         N      Ceftriaxone+                                  __________________________________________________________________________    P. aeruginosa  8710                                                                       1738     41  50     28 + 28                                       __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________                PD.sub.50 : MG/kg sc.sup.1                                        __________________________________________________________________________                             10 + 1                                                                        Ampicillin                                                                    +       FIC  Synergy rating                          Infecting Organism                                                                        Ampicillin                                                                           I     I       10 + 1                                                                             10 + 1                                  __________________________________________________________________________    E. coli 736  5     0.05  0.058 + 0.058                                                                         0.128                                                                              ++++                                    K. pneumoniae 503-990A                                                                    (1) 58 <2    3.1 + 0.31                                                                            >0.208                                                   (2) 10 <2     <2 + <0.2                                                                            0.300                                        K. pneumoniae 39                                                                          36     115    <2 + <0.2                                                                            0.058                                                                              ++++                                    __________________________________________________________________________                             10 + 1                                                                        Cephalothin                                                                   +                                                                Cephalothin                                                                          I     I                                                    __________________________________________________________________________    E. coli BC5524                                                                            >250   >250  87 + 8.7                                                                              0.383                                                                              +++                                     K. pneumoniae R2296                                                                       93     >250  31 + 3.1                                                                              0.345                                                                              +++                                     E. cloacae 4633                                                                           >250   6.4   31 + 3.1                                                                              0.608                                                                              NS                                      __________________________________________________________________________

We claim:
 1. A compound of the formula ##STR44## wherein n is an integerfrom 0 to 1; R₁ is hydrogen or lower alkyl; ##STR45## is a saturated 5to 7 membered heterocyclic ring containing the nitrogen atom as the onlyhetero atom in said ring, said ring being unsubstituted or substitutedin one or more positions with lower alkyl; ##STR46## is a 5 to 7membered heterocyclic ring which contains no additional double bond orwhen it is 5 membered can be also aromatic; said ring being eitherunsubstituted or substituted in one or more positions with lower alkyl;R₁₂ and R₁₃ are lower alkyl or taken together form --CH₂ -- --(CH₂)_(x)--CH₂ --; x is an integer from 0 to 2; and R₇ is lower alkylene.
 2. Thecompound of claim 1 wherein said compound is4-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-1-piperidine carboxaldehydedimethyl acetal.
 3. The compound of claim 1 wherein said compound is4-(1H-imidazol-2-yl)-1-piperidine carboxaldhyde dimethyl acetal.